AU2013263832A1 - Prognosis prediction for colorectal cancer - Google Patents

Abstract

This invention relates to prognostic signatures, compositions and methods for determining the prognosis of cancer in a patient, particularly for colorectal cancer. Specifically, this invention relates to the use of genetic markers for the prediction of the prognosis of cancer, such as colorectal cancer, based on signatures of genetic markers.

Description

WO 2007/073220 PCT/NZ2006/000343 PROGNOSIS PREDICTION FOR COLORECTAL CANCER RELATED APPLICATION 5 This application claims the benefit of New Zealand Provisional Patent Application No. 544432 filed December 23, 2005, which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION 10 This invention relates to methods and compositions for determining the prognosis of cancer, particularly colorectal cancer, in a patient. Specifically, this invention relates to the use of genetic markers for determining the prognosis of cancer, such as colorectal cancer, based on prognostic signatures. 15 BACKGROUND OF THE INVENTION Colorectal cancer (CRC) is one of the most common cancers in the developed world, and its incidence is continuing to increase. Although the progression of colorectal cancer from benign polyp to adenoma to carcinoma is well studied (1), the molecular events influencing the transition and establishment of metastasis are less well 20 understood. The prognosis and treatment of CRC currently depends on the clinico pathological stage of disease at the time of diagnosis, and primary surgical treatment. Unfortunately disease stage alone does not allow accurate prediction of outcome for individual patients. If patient outcomes could be predicted more accurately treatments could be tailored to avoid under-treating patients destined to relapse, or over-treating 25 patients who would be helped by surgery alone. Many attempts have been made to identify markers that predict clinical outcome in CRC. Until recently most studies focused on single proteins or gene mutations with limited success in terms of prognostic information (2). Microarray technology 30 enables the identification of sets of genes, called classifiers or signatures that correlate with cancer outcome. This approach has been applied to a variety of cancers, including CRC (3-5), but methodological problems and a lack of independent validation has cast doubt over the findings (6,7). Furthermore, doubts about the ability of classifiers/signatures to predict outcome have arisen due to poor 1 WO 2007/073220 PCT/NZ2006/000343 concordance of identified by different researchers using different array platforms and methodologies (8). There is a need for further tools to predict the prognosis of colorectal cancer. This 5 invention provides further methods, compositions, kits, and devices based on prognostic cancer markers, specifically colorectal cancer prognostic markers, to aid in the prognosis and treatment of cancer. SUMMARY OF THE INVENTION 10 In certain embodiments there is provided a set of markers genes identified to be differentially expressed in recurrent and non-recurrent colorectal tumours. This set of genes can be used to generate prognostics signatures, comprising two or more markers, capable of predicting the progression of colorectal tumour in a patient. 15 The individual markers can differentially expressed depending on whether the tumour is recurrent or not. The accuracy of prediction can be enhanced by combining the markers together into a prognostic signature for, providing for much more effective individual tests than single-gene assays. Also provided for is the application of techniques, such as statistics, machine learning, artificial intelligence, and data mining 20 to the prognostics signatures to generate prediction models. In another embodiment, expression levels of the markers of a particular prognostic signature in the tumour of a patient can then be applied to the prediction model to determine the prognosis. In certain embodiments, the expression level of the markers can be established using 25 microarray methods, quantitative polymerase chain reaction (qPCR), or immunoassays. BRIEF DESCRIPTION OF THE FIGURES This invention is described with reference to specific embodiments thereof and 30 with reference to the figures, in which: Figure 1 depicts a flow chart showing the methodology for producing the prognostic signatures from 149 New Zealand (NZ) and 55 German (DE) colorectal cancer (CRC) samples. New Zealand RNA samples were hybridized to 2 WO 2007/073220 PCT/NZ2006/000343 oligonucleotide spotted arrays, with a 22-gene signature produced via leave one out cross validation (LOOCV), and then independently validated by LOOCV using the 55 sample DE data set. German RNA samples were hybridized to Affymetrix arrays, with a 19-gene signature produced via LOOCV, and then independently validated by 5 LOOCV using the NZ data set. Figure 2 depicts a Kaplan-Meier analysis of disease-free survival time with patients predicted as high versus low risk of tumour recurrence: a, using NZ 22-gene signature on 149 tumours from NZ patients; b, using DE 19-gene signature on 55 10 tumours from DE patients; c, NZ prognostic signature validated on 55 tumours from DE patients; d, DE prognostic signature validated on 149 tumours from NZ patients. P-values were calculated using the log-rank test. Figure 3 depicts a Kaplan-Meier analysis of disease free survival time with 15 patients predicted as high versus low risk of tumour recurrence: a, using the 22-gene NZ signature on NZ patients with Stage II and Stage III disease; b, using the19-gene DE signature on NZ patients with Stage II and Stage III disease. Figure 4 shows the predictive value of signatures of varying lengths for 20 prognosis of colorectal cancer. These signatures were derived from 10 replicate runs of 11-fold cross validation. Each replicate 11-fold validation run is indicated by the various dashed lines; the mean across replicates by the bold line. In each fold of the cross-validation, genes were removed if the fold-change across classes was < 1.1 (for the remaining samples not removed in that particular fold). The genes were then 25 ranked using a modified t-statistic, obtaining a different set of genes for each fold, and classifiers using the top n- genes (where n=2 to 200) were constructed for each fold. The genes therefore may differ for each fold of each replicate 11-fold cross validation. Figure 4 (A): Sensitivity (proportion of recurrent tumours correctly classified), with respect to number of genes/signature. Figure 4 (B): Specificity (proportion of non 30 recurrent tumours correctly classified), with respect to number of genes/signature. Figure 4 (C): Classification rate (proportion of tumours correctly classified), with respect to number of genes/signature. The nomenclature applied by the statistician is as follows: I refers to Stage I or Stage II colorectal cancer (with no progression), and IV refers to eventual progression to Stage IV metastases. 3 WO 2007/073220 PCT/NZ2006/000343 Figure 5 shows the decreased predictive value of signatures for the prognosis of colorectal cancer, in a repeat of the experiment of Figure 4, except with the two genes, FAS and ME2,removed from the data set. Figure 5 (A): Sensitivity (proportion 5 of recurrent tumours correctly classified), with respect to number of genes/signature. Figure 5 (B): Specificity (proportion of non-recurrent tumours correctly classified), with respect to number of genes/signature. Figure 5 (C): Classification rate (proportion of tumours correctly classified), with respect to number of genes/signature. 10 Figure 6 shows a pairs chart of "top counts" (number of times each gene appeared in the "top-n" gene lists, i.e., top 10, top 20, top 100, and top 325 as described in Example 17) using three different normalization methods produced using the R statistical computing package(10,39) , in accordance with Example 17, below. 15 The "pairs" chart is described in by Becker et al, in their treatise on the S Language (upon which R is based; see reference 39) To compare methods, use row and column as defined on the diagonal to obtain the scatter plot between those two methods, analogous to reading distances off a distance chart on a map 20 Figure 7 shows the pairs chart (39) of top counts (number of times each gene appeared in the "top-n" gene lists, i.e., top 10, top 20, top 100, and top 325 as described in Example 17) using three different filtering statistics: (a) two-sample Wilcoxon test (41), (b) t-test (modified using an ad-hoc correction factor in the denominator to abrogate the effect of low-variance genes falsely appearing as 25 significant) and (c) empirical Bayes as provided by the "limma"(10,40,42) package of Bioconductor (12,40). DETAILED DESCRIPTION Definitions 30 Before describing embodiments of the invention in detail, it will be useful to provide some definitions of terms used herein. The term "marker" refers to a molecule that is associated quantitatively or qualitatively with the presence of a biological phenomenon. Examples of "markers" 4 WO 2007/073220 PCT/NZ2006/000343 include a polynucleotide, such as a gene or gene fragment, RNA or RNA fragment; or a gene product, including a polypeptide such as a peptide, oligopeptide, protein, or protein fragment; or any related metabolites, by products, or any other identifying molecules, such as antibodies or antibody fragments, whether related directly or 5 indirectly to a mechanism underlying the phenomenon. The markers of the invention include the nucleotide sequences (e.g., GenBank sequences) as disclosed herein, in particular, the full-length sequences, any coding sequences, any fragments, or any complements thereof, and any measurable marker thereof as defined above. 10 The terms "CCPM" or "colorectal cancer prognostic marker" or "CCPM family member" refer to a marker with altered expression that is associated with a particular prognosis, e.g., a higher or lower likelihood of recurrence of cancer, as described herein, but can exclude molecules that are known in the prior art to be associated with prognosis of colorectal cancer. It is to be understood that the term CCPM does not 15 require that the marker be specific only for colorectal tumours. Rather, expression of CCPM can be altered in other types of tumours, including malignant tumours. The terms "prognostic signature," "signature," and the like refer to a set of two or more markers, for example CCPMs, that when analysed together as a set allow for the 20 determination of or prediction of an event, for example the prognostic outcome of colorectal cancer. The use of a signature comprising two or more markers reduces the effect of individual variation and allows for a more robust prediction. Non-limiting examples of CCPMs are set forth in Tables 1, 2, 5, and 9, while non-limiting examples of prognostic signatures are set forth in Tables 3, 4, 8A, 8B, and 9, herein. In the 25 context of the present invention, reference to "at least one," "at least two," "at least five," etc., of the markers listed in any particular set (e.g., any signature) means any one or any and all combinations of the markers listed. The term "prediction method" is defined to cover the broader genus of methods from 30 the fields of statistics, machine learning, artificial intelligence, and data mining, which can be used to specify a prediction model. These are discussed further in the Detailed Description section. 5 WO 2007/073220 PCT/NZ2006/000343 The term "prediction model" refers to the specific mathematical model obtained by applying a prediction method to a collection of data. In the examples detailed herein, such data sets consist of measurements of gene activity in tissue samples taken from recurrent and non-recurrent colorectal cancer patients, for which the class (recurrent 5 or non-recurrent) of each sample is known. Such models can be used to (1) classify a sample of unknown recurrence status as being one of recurrent or non-recurrent, or (2) make a probabilistic prediction (i.e., produce either a proportion or percentage to be interpreted as a probability) which represents the likelihood that the unknown sample is recurrent, based on the measurement of mRNA expression levels or expression 10 products, of a specified collection of genes, in the unknown sample. The exact details of how these gene-specific measurements are combined to produce classifications and probabilistic predictions are dependent on the specific mechanisms of the prediction method used to construct the model. 15 "Sensitivity", "specificity" (or "selectivity"), and "classification rate", when applied to the describing the effectiveness of prediction models mean the following: "Sensitivity" means the proportion of truly positive samples that are also predicted (by the model) to be positive. In a test for CRC recurrence, that would be the proportion of recurrent tumours predicted by the model to be recurrent. "Specificity" or 20 "selectivity" means the proportion of truly negative samples that are also predicted (by the model) to be negative. In a test for CRC recurrence, this equates to the proportion of non-recurrent samples that are predicted to by non-recurrent by the model. "Classification Rate" is the proportion of all samples that are correctly classified by the prediction model (be that as positive or negative). 25 As used herein "antibodies" and like terms refer to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. These include, but are not limited to, polyclonal, monoclonal, chimeric, 30 single chain, Fc, Fab, Fab', and Fab 2 fragments, and a Fab expression library. Antibody molecules relate to any of the classes IgG, IgM, IgA, IgE, and IgD, which differ from one another by the nature of heavy chain present in the molecule. These include subclasses as well, such as IgGl, IgG2, and others. The light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to 6 WO 2007/073220 PCT/NZ2006/000343 all classes, subclasses, and types. Also included are chimeric antibodies, for example, monoclonal antibodies or fragments thereof that are specific to more than one source, e.g., a mouse or human sequence. Further included are camelid antibodies, shark antibodies or nanobodies. 5 The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. Cancer and cancer pathology can be associated, for example, with metastasis, interference with the normal functioning of neighbouring cells, release of cytokines or 10 other secretory products at abnormal levels, suppression or aggravation of inflammatory or immunological response, neoplasia, premalignancy, malignancy, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc. Specifically included are colorectal cancers, such as, bowel (e.g., large bowel), anal, and rectal cancers. 15 The term "colorectal cancer" includes cancer of the colon, rectum, and/or anus, and especially, adenocarcinomas, and may also include carcinomas (e.g., squamous cloacogenic carcinomas), melanomas, lymphomas, and sarcomas. Epidermoid (nonkeratinizing squamous cell or basaloid) carcinomas are also included. The cancer 20 may be associated with particular types of polyps or other lesions, for example, tubular adenomas, tubulovillous adenomas (e.g., villoglandular polyps), villous (e.g., papillary) adenomas (with or without adenocarcinoma), hyperplastic polyps, hamartomas, juvenile polyps, polypoid carcinomas, pseudopolyps, lipomas, or leiomyomas. The cancer may be associated with familial polyposis and related 25 conditions such as Gardner's syndrome or Peutz-Jeghers syndrome. The cancer may be associated, for example, with chronic fistulas, irradiated anal skin, leukoplakia, lymphogranuloma venereum, Bowen's disease (intraepithelial carcinoma), condyloma acuminatum, or human papillomavirus. In other aspects, the cancer may be associated with basal cell carcinoma, extramammary Paget's disease, cloacogenic carcinoma, or 30 malignant melanoma. The terms "differentially expressed," "differential expression," and like phrases, refer to a gene marker whose expression is activated to a higher or lower level in a subject (e.g., test sample) having a condition, specifically cancer, such as colorectal cancer, 7 WO 2007/073220 PCT/NZ2006/000343 relative to its expression in a control subject (e.g., reference sample). The terms also include markers whose expression is activated to a higher or lower level at different stages of the same condition; in recurrent or non-recurrent disease; or in cells with higher or lower levels of proliferation. A differentially expressed marker may be 5 either activated or inhibited at the polynucleotide level or polypeptide level, or may be subject to alternative splicing to result in a different polypeptide product. Such differences may be evidenced by a change in mRNA levels, surface expression, secretion or other partitioning of a polypeptide, for example. 10 Differential expression may include a comparison of expression between two or more markers (e.g., genes or their gene products); or a comparison of the ratios of the expression between two or more markers (e.g., genes or their gene products); or a comparison of two differently processed products (e.g., transcripts or polypeptides) of the same marker, which differ between normal subjects and diseased subjects; or 15 between various stages of the same disease; or between recurring and non-recurring disease; or between cells with higher and lower levels of proliferation; or between normal tissue and diseased tissue, specifically cancer, or colorectal cancer. Differential expression includes both quantitative, as well as qualitative, differences in the temporal or cellular expression pattern in a gene or its expression products among, for 20 example, normal and diseased cells, or among cells which have undergone different disease events or disease stages, or cells with different levels of proliferation. The term "expression" includes production of polynucleotides and polypeptides, in particular, the production -of RNA (e.g., mRNA) from a gene or portion of a gene, and 25 includes the production of a polypeptide encoded by an RNA or gene or portion of a gene, and the appearance of a detectable material associated with expression. For example, the formation of a complex, for example, from a polypeptide-polypeptide interaction, polypeptide-nucleotide interaction, or the like, is included within the scope of the term "expression". Another example is the binding of a binding ligand, such as 30 a hybridization probe or antibody, to a gene or other polynucleotide or oligonucleotide, a polypeptide or a protein fragment, and the visualization of the binding ligand. Thus, the intensity of a spot on a microarray, on a hybridization blot such as a Northern blot, or on an immunoblot such as a Western blot, or on a bead 8 WO 2007/073220 PCT/NZ2006/000343 array, or by PCR analysis, is included within the term "expression" of the underlying biological molecule. The terms "expression threshold," and "defined expression threshold" are used 5 interchangeably and refer to the level of a marker in question outside which the polynucleotide or polypeptide serves as a predictive marker for patient survival without cancer recurrence. The threshold will be dependent on the predictive model established are derived experimentally from clinical studies such as those described in the Examples below. Depending on the prediction model used, the expression 10 threshold may be set to achieve maximum sensitivity, or for maximum specificity, or for minimum error (maximum classification rate). For example a higher threshold may be set to achieve minimum errors, but this may result in a lower sensitivity. Therefore, for any given predictive model, clinical studies will be used to set an expression threshold that generally achieves the highest sensitivity while having a 15 minimal error rate. The determination of the expression threshold for any situation is well within the knowledge of those skilled in the art. The term "long-term survival" is used herein to refer to survival for at least 5 years, more preferably for at least 8 years, most preferably for at least 10 years 20 following surgery or other treatment. The term "microarray" refers to an ordered or unordered arrangement of capture agents, preferably polynucleotides (e.g., probes) or polypeptides on a substrate. See, e.g., Microarray Analysis, M. Schena, John Wiley & Sons, 2002; Microarray Biochip 25 Technology, M. Schena, ed., Eaton Publishing, 2000; Guide to Analysis of DNA Microarray Data, S. Knudsen, John Wiley & Sons, 2004; and Protein Microarray Technology, D. Kambhampati, ed., John Wiley & Sons, 2004. The term "oligonucleotide" refers to a polynucleotide, typically a probe or primer, 30 including, without limitation, single-stranded deoxyribonucleotides, single- or double stranded ribonucleotides, RNA: DNA hybrids, and double-stranded DNAs. Oligonucleotides, such as single-stranded DNA probe oligonucleotides, are often synthesized by chemical methods, for example using automated oligonucleotide synthesizers that are commercially available, or by a variety of other methods, 9 WO 2007/073220 PCT/NZ2006/000343 including in vitro expression systems, recombinant techniques, and expression in cells and organisms. The term "polynucleotide," when used in the singular or plural, generally refers to any 5 polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. This includes, without limitation, single- and double-stranded DNA, DNA including single- and double- stranded regions, single and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more 10 typically, double-stranded or include single- and double-stranded regions. Also included are triple-stranded regions comprising RNA or DNA or both RNA and DNA. Specifically included are mRNAs, cDNAs, and genomic DNAs, and any fragments thereof. The term includes DNAs and RNAs that contain one or more modified bases, such as tritiated bases, or unusual bases, such as inosine. The polynucleotides of the 15 invention can encompass coding or non-coding sequences, or sense or antisense sequences. It will be understood that each reference to a "polynucleotide" or like term, herein, will include the full-length sequences as well as any fragments, derivatives, or variants thereof. 20 "Polypeptide," as used herein, refers to an oligopeptide, peptide, or protein sequence, or fragment thereof, and to naturally occurring, recombinant, synthetic, or semi synthetic molecules. Where "polypeptide" is recited herein to refer to an amino acid sequence of a naturally occurring protein molecule, "polypeptide" and like terms, are not meant to limit the amino acid sequence to the complete, native amino acid 25 sequence for the full-length molecule. It will be understood that each reference to a "polypeptide" or like term, herein, will include the full-length sequence, as well as any fragments, derivatives, or variants thereof. The term "prognosis" refers to a prediction of medical outcome, for example, a poor or 30 good outcome (e.g., likelihood of long-term survival); a negative prognosis, or poor outcome, includes a prediction of relapse, disease progression (e.g., tumour growth or metastasis, or drug resistance), or mortality; a positive prognosis, or good outcome, includes a prediction of disease remission, (e.g., disease-free status), amelioration (e.g., tumour regression), or stabilization. 10 WO 2007/073220 PCT/NZ2006/000343 The term "proliferation" refers to the processes leading to increased cell size or cell number, and can include one or more of: tumor or cell growth, angiogenesis, innervation, and metastasis. 5 The term "qPCR" or "QPCR" refers to quantative polymerase chain reaction as described, for example, in PCR Technique: Quantitative PCR, J.W. Larrick, ed., Eaton Publishing, 1997, and A-Z of Quantitative PCR, S. Bustin, ed., IUL Press, 2004. 10 The term "tumour" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. "Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon 15 probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe 20 and hybridisable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. Additional details and explanation of stringency of hybridization reactions, are found e.g., in Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995). 25 "Stringent conditions" or "high stringency conditions", as defined herein, typically: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50'C; (2) employ a denaturing agent during hybridization, such as 30 formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42'C; or (3) employ 50% formamide, 5X SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5X, Denhardt's solution, sonicated salmon sperm DNA 11 WO 2007/073220 PCT/NZ2006/000343 (50 pg/ml), 0.1% SDS, and 10% dextran sulfate at 42-C, with washes at 42 0 C in 0.2X SSC (sodium chloride/sodium citrate) and 50% formamide at 55 0 C, followed by a high-stringency wash comprising 0.lX SSC containing EDTA at 55 0 C. 5 "Moderately stringent conditions" may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e. g., temperature, ionic strength, and % SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37"C in a 10 solution comprising: 20% formamide, 5X SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5X Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1X SSC at about 37-50'C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe 15 length and the like. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, and biochemistry, which are within the skill of the art. 20 Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, 2nd edition, Sambrook et al., 1989; Oligonucleotide Synthesis, MJ Gait, ed., 1984; Animal Cell Culture, R.I. Freshney, ed., 1987; Methods in Enzymology, Academic Press, Inc.; Handbook of Experimental Immunology, 4th edition, D .M. Weir & CC. Blackwell, eds., Blackwell Science Inc., 1987; Gene 25 Transfer Vectors for Mammalian Cells, J.M. Miller & M.P. Calos, eds., 1987; Current Protocols in Molecular Biology, F.M. Ausubel et al., eds., 1987; and PCR: The Polymerase Chain Reaction, Mullis et al., eds., 1994. Description of Embodiments of the Invention 30 In colorectal cancer, discordant results have been reported for prognostic markers. The present invention discloses the use of microarrays to reach a firmer conclusion, and to determine the prognostic role of specific prognostic signatures in colorectal cancer. The microarray-based studies shown herein indicate that particular prognostic signatures in colorectal cancer are associated with a prognosis. The 12 WO 2007/073220 PCT/NZ2006/000343 invention can therefore be used to identify patients at high risk of recurrence of cancer, or patients with a high likelihood of recovery. The present invention provides for markers for the determination of disease prognosis, 5 for example, the likelihood of recurrence of tumours, including colorectal tumours. Using the methods of the invention, it has been found that numerous markers are associated with the prognosis of colorectal cancer, and can be used to predict disease outcome. Microarray analysis of samples taken from patients with various stages of colorectal tumours has led to the surprising discovery that specific patterns of marker 10 expression are associated with prognosis of the cancer. The present invention therefore provides for a set of genes, outlined in Table 1 and Table 2, that are differentially expressed in recurrent and non-recurrent colorectal cancers. The genes outlined in Table 1 and Table 2 provide for a set of colorectal cancer prognostic makers (CCPMs). 15 A decrease in certain colorectal cancer prognostic markers (CCPMs), for example, markers associated with immune responses, is indicative of a particular prognosis. This can include increased likelihood of cancer recurrence after standard treatment, especially for colorectal cancer. Conversely, an increase in other CCPMs is indicative 20 of a particular prognosis. This can include disease progression or the increased likelihood of cancer recurrence, especially for colorectal cancer. A decrease or increase in expression can be determined, for example, by comparison of a test sample, e.g., patient's tumour sample, to a reference sample, e.g., a sample associated with a known prognosis. In particular, one or more samples from patient(s) with non 25 recurrent cancer could be used as a reference sample. For example, to obtain a prognosis, expression levels in a patient's sample (e.g., tumour sample) can be compared to samples from patients with a known outcome. If the patient's sample shows increased or decreased expression of one or more CCPMs 30 that compares to samples with good outcome (no recurrence), then a positive prognosis, or recurrence is unlikely, is implicated. If the patient's sample shows expression of one or more CCPMs that is comparable to samples with poor outcome (recurrence), then a positive prognosis, or recurrence of the tumour is likely, is implicated. 13 WO 2007/073220 PCT/NZ2006/000343 As further examples, the expression levels of a prognostic signature comprising two or more CCPMS from a patient's sample (e.g., tumour sample) can be compared to samples of recurrent/non-recurrent cancer. If the patient's sample shows increased or 5 decreased expression of CCPMs by comparison to samples of non-recurrent cancer, and/or comparable expression to samples of recurrent cancer, then a negative prognosis is implicated. If the patient's sample shows expression of CCPMs that is comparable to samples of non-recurrent cancer, and/or lower or higher expression than samples of recurrent cancer, then a positive prognosis is implicated. 10 As one approach, a prediction method can be applied to a panel of markers, for example the panel of CCPMs outlined in Table 1 and Table 2, in order to generate a predictive model. This involves the generation of a prognostic signature, comprising two or more CCPMs. 15 The disclosed CCPMs in Table 1 and Table 2 therefore provide a useful set of markers to generate prediction signatures for determining the prognosis of cancer, and establishing a treatment regime, or treatment modality, specific for that tumour. In particular, a positive prognosis can be used by a patient to decide to pursue standard or 20 less invasive treatment options. A negative prognosis can be used by a patient to decide to terminate treatment or to pursue highly aggressive or experimental treatments. In addition, a patient can chose treatments based on their impact on the expression of prognostic markers (e.g., CCPMs). 25 Levels of CCPMs can be detected in tumour tissue, tissue proximal to the tumour, lymph node samples, blood samples, serum samples, urine samples, or faecal samples, using any suitable technique, and can include, but is not limited to, oligonucleotide probes, quantitative PCR, or antibodies raised against the markers. It will be appreciated that by analyzing the presence and amounts of expression of a plurality of 30 CCPMs in the form of prediction signatures, and constructing a prognostic signature (e.g., as set forth in Tables 3, 4, 8A, 8B, and 9), the sensitivity and accuracy of prognosis will be increased. Therefore, multiple markers according to the present invention can be used to determine the prognosis of a cancer. 14 WO 2007/073220 PCT/NZ2006/000343 The invention includes the use of archived paraffin-embedded biopsy material for assay of the markers in the set, and therefore is compatible with the most widely available type of biopsy material. It is also compatible with several different methods of tumour tissue harvest, for example, via core biopsy or fine needle aspiration. In 5 certain aspects, RNA is isolated from a fixed, wax-embedded cancer tissue specimen of the patient. Isolation may be performed by any technique known in the art, for example from core biopsy tissue or fine needle aspirate cells. In one aspect, the invention relates to a method of predicting a prognosis, e.g., the 10 likelihood of long-term survival of a cancer patient without the recurrence of cancer, comprising determining the expression level of one or more prognostic markers or their expression products in a sample obtained from the patient, normalized against the expression level of other RNA transcripts or their products in the sample, or of a reference set of RNA transcripts or their expression products. In specific aspects, the 15 prognostic marker is one or more markers listed in Tables 1, 2, or 5, , or is included as one or more of the prognostic signatures derived from the markers listed in Tables 1, 2, and 5, or the prognostic signatures listed in Tables 3, 4, 8A, 8B, or 9. In further aspects, the expression levels of the prognostic markers or their expression 20 products are determined, e.g., for the markers listed in Tables 1, 2, or 5, a prognostic signature derived from the markers listed in Tables 1, 2, and 5, e.g., for the prognostic signatures listed in Tables 3, 4, 8A, 8B, or 9. In another aspect, the method comprises the determination of the expression levels of a full set of prognosis markers or their expression products, e.g., for the markers listed in Tables 1, 2, or 5, or, a prognostic 25 signature derived from the markers listed in Tables 1, 2, and 5, e.g., for the prognostic signatures listed in Tables 3, 4, 8A, 8B, or 9. In an additional aspect, the invention relates to an array (e.g., microarray) comprising polynucleotides hybridizing to two or more markers, e.g., for the markers listed in 30 Tables 1, 2, and 5, , or a prognostic signature derived from the markers listed in Tables 1, 2, and 5, e.g., the prognostic signatures listed in Tables 3, 4, 8A, 8B, and 9. In particular aspects, the array comprises polynucleotides hybridizing to prognostic signature derived from the markers listed in Tables 1, 2, and 5, or e.g., for the prognostic signatures listed in Tables 3, 4, 8A, 8B, or 9. In another specific aspect, the 15 WO 2007/073220 PCT/NZ2006/000343 array comprises polynucleotides hybridizing to the full set of markers, e.g., for the markers listed in Tables 1, 2, or 5, or, e.g., for the prognostic signatures listed in Tables 3, 4, 8A, 8B, or 9. 5 For these arrays, the polynucleotides can be cDNAs, or oligonucleotides, and the solid surface on which they are displayed can be glass, for example. The polynucleotides can hybridize to one or more of the markers as disclosed herein, for example, to the full-length sequences, any coding sequences, any fragments, or any complements thereof. In particular aspects, an increase or decrease in expression levels of one or 10 more CCPM indicates a decreased likelihood of long-term survival, e.g., due to cancer recurrence, while a lack of an increase or decrease in expression levels of one or more CCPM indicates an increased likelihood of long-term survival without cancer recurrence. 15 Table 1: Colorectal Cancer Predictive Markers (corresponding to Affymetrix GeneChip probes that show statistically significant differential expression, P<0.05, as ascertained by BRB Array Tools) Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) ME2 210154 at, NM 002396 malic enzyme 2, NAD(+)- Hs.233119 M55905, 0.74 210153_s_at, dependent, mitochondrial BC000147 209397_at STATI AFFX- NM_007315, signal transducer and Hs.470943 NM 007315, 0.58 HLUMISGF3 NM_139266 activator of transcription 1, BC002704 A/ 91kDa M97935_MA _at,

AFFX

HUMISGF3 A/ M97935_MB _at,

AFFX

HUMISGF3 A/ M97935_3_at ,200887_sat,

AFFX

HUMISGF3 A/ 16 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) M97935_5_at 209969 s at CXCL10 204533 at NM 001565 chemokine (C-X-C motif) Hs.413924 NM_001565 0.29 ligand 10 FAS 215719x_at, NM_000043, Fas (TNF receptor Hs.244139 X83493, 0.68 216252_x_at, NM_152871, superfamily, member 6) Z70519, 204780 sat, NM_152872, AA164751, 204781 s at NM152873, NM000043 NM152874, NM_152875, NM_152876, NM152877 SFRS2 200753_x at, NM_003016 splicing factor, Hs.73965 BE866585, 0.82 214882 s at, arginine/serine-rich 2 BG254869, 200754_x at NM_003016 GUFI 218884_s at. NM_021927 GUF1 GTPase homolog (S. Hs.546419 NM_021927 0.71 cerevisiae) CXCL9 203915_at NM_002416 chemokine (C-X-C motif) Hs.77367 NM002416 0.33 ligand 9 TYMS 202589 at NM 001071 thymidylate synthetase Hs.369762 NM_001071 0.53 SEC10L1 218748_s at NM_006544 SEC10-like 1 (S. cerevisiae) Hs.365863 NM_006544 0.76 PLK4 204887 s at NM_014264 polo-like kinase 4 Hs.172052 NM_014264 0.64 (Drosophila) MAP2K4 203265 s at NM_003010 mitogen-activated protein Hs.514681 AA810268 0.76 kinase kinase 4 EIF4E 201435 s at, NM 001968 eukaryotic translation Hs.249718 AW268640, 0.69 201436_at initiation factor 4E A1742789 TLK1 210379 s at NM 012290 tousled-like kinase 1 Hs.470586 AF162666 0.59 CXCL11 210163_ at, NM_005409 chemokine (C-X-C motif) Hs.518814 AF030514,A 0.15 211122 s at ligand I1 F002985 PSME2 201762_s_at NM_002818 proteasome (prosome, Hs.434081, NM_002818 0.68 macropain) activator subunit Hs.512410 2 (PA28 beta) hCAP-D3 212789_at NM_015261 non-SMC condensin II Hs.438550 A1796581 0.83 complex, subunit D3 MPP5 219321_at NM_022474 membrane protein, Hs.509699 NM_022474 0.74 palmitoylated 5 (MAGUK p55 subfamily member 5) DLGAP4 202570_s at NM 014902, discs, large (Drosophila) Hs.249600 BF346592 1.3 NM_183006 homolog-associated protein 4 17 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) WARS 200628_s at, NM_004184, tryptophanyl-tRNA Hs.497599 M61715, 0.66 200629_at NM_173701, synthetase NM_004184 NM_213645, NM_213646 ARF6 203312_x at NM_001663 ADP-ribosylation factor 6 Hs.525330 NM_001663 0.77 PBK 219148_at NM_018492 PDZ binding kinase Hs.104741 NM_018492 0.41 GMFB 202543 s at NM_004124 glia maturation factor, beta Hs.151413 BC005359 0.66 NDUFA9 208969_at NM_005002 NADH dehydrogenase Hs.75227 AF050641 0.77 (ubiquinone) 1 alpha subcomplex, 9, 39kDa CDC40 203377_s_at NM_015891 cell division cycle 40 Hs.428147 NM015891 0.8 homolog (yeast) WHSC1 209053 s at, NM_007331, Wolf-Hirschhorn syndrome Hs.113876 BE793789, 0.75 209054_sat, NM_014919, candidate 1 AF083389, 209052_s at NM 133330, BF111870 NM_133331, NM_133332, NM_133333, NM_133334, NM_133335, NM_133336 C1QBP 208910_sat, NM_001212 complement component 1, q Hs.555866 L04636, 0.71 214214_s at subcomponent binding AU151801 protein RBM25 212031_at NM 021239 RNA binding motif protein 25 Hs.531106 AV757384 0.83 SLC25Al 1 209003_at, NM_003562 solute carrier family 25 Hs.184877 AF070548, 0.83 207088 s at (mitochondrial carrier, NM_003562 oxoglutarate carrier), member 11 TK1 202338_at NM_003258 thymidine kinase 1, soluble Hs.515122 NM_003258 0.73 ETNK1 222262 s at, NM 018638 ethanolamine kinase 1 Hs.240056 AL137750, 0.66 219017_at NM_018638 KLHL24 221985 at NM_017644 kelch-like 24 (Drosophila) Hs.407709 AW006750 1.4 AK2 212175_s at, NM_001625, adenylate kinase 2 Hs.470907 AL513611, 0.8 205996_s at, NM 013411 NM 013411, 212174 at W2312 HNRPD 221481 _xat, NM0010038 heterogeneous nuclear Hs.480073 D55672, 0.8 209330_s at, 10,NM_00213 ribonucleoprotein D (AU-rich D55674, 200073 s at 8, element RNA binding protein M94630 NM 031369, 1, 37kDa) NM_031370 18 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) GTPBP3 213835_x_at NM_032620, GTP binding protein 3 Hs.334885 AL524262 0.87 NM 133644 (mitochondrial) PSATI 220892_s_at NM_021154, phosphoserine Hs.494261 NM_021154 0.54 NM_058179 aminotransferase 1 AP1G1 203350_at NM 0010300 adaptor-related protein Hs.461253 NM_001128 0.89 07,NM_00112 complex 1, gamma 1 subunit 8 SMCHD1 212577_at structural maintenance of Hs.8118 AA868754 0.74 chromosomes flexible hinge domain containing 1 SLC4A4 210738_s_at, NM_003759 solute carrier family 4, Hs.5462 AF011390, 0.7 203908_at sodium bicarbonate NM 003759, 211494_s at, cotransporter, member 4 AF157492, 210739_x at AF069510 RBMS3 206767_at NM_0010037 RNA binding motif, single Hs.221436 NM_014483 1.2 92,NM_00100 stranded interacting protein 3793,NM_014 483 LARP4 214155_s_at NM_052879, La ribonucleoprotein domain Hs.26613 A1743740 0.66 NM_199188, family, member 4 NM_199190 FANCA 203805_s_at NM_000135, Fanconi anemia, Hs.284153 AW083279 0.78 NM_0010181 complementation group A 12 SOS1 212780_at NM_005633 son of sevenless homolog 1 Hs.278733 AA700167 0.84 (Drosophila) IFT20 210312_s_at NM_174887 intraflagellar transport 20 Hs.4187 BC002640 1.2 homolog (Chlamydomonas) NUP210 212316_at, NM_024923 nucleoporin 21OkDa Hs.475525 AA502912,- 0.78 220035_at, NM_024923, 213947_s at A1867102 IRF8 204057_at NM_002163 interferon regulatory factor 8 Hs.137427 AI073984 0.75 SGPP1 221268 s_at NM_030791 sphingosine-1-phosphate Hs.24678 NM_030791 0.76 phosphatase 1 MAD2L1 203362_s at NM_002358 MAD2 mitotic arrest Hs.509523, NM_002358 0.7 deficient-like 1 (yeast) Hs.533185 PAICS 201013_s_at, NM_006452 phosphoribosylaminoimidazol Hs.518774 AA902652, 0.71 201014_s_at e carboxylase, NM_006452 phosphoribosylaminoimidazol e succinocarboxamide synthetase RPS2 217466_x_at NM_002952 ribosomal protein S2 Hs.356366, L48784 0.83 Hs.381079, Hs.498569, Hs.506997, Hs.556270 19 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) TMEDS 202195_s_at NM_016040 transmembrane emp24 Hs.482873 NM_016040 0.86 protein transport domain containing 5 GTSE1 204317_at, NM_016426 G-2 and S-phase expressed 1 Hs.386189, BF305380, 0.8 204318_s_at Hs.475140 NM_016426 DCK 203302_at NM_000788 deoxycytidine kinase Hs.709 NM_000788 0.77 DKFZp762E13 218726_at NM_018410 hypothetical protein Hs.532968 NM_018410 0.81 12 DKFZp762E1312 BAZIA 217986_s_at NM013448, bromodomain adjacent to zinc Hs.509140 NM013448 0.8 NM_182648 finger domain, 1A HIP2 202346_at NM_005339 huntingtin interacting protein Hs.50308 NM_005339 0.78 2 HNRPA3P1 206809_s_at heterogeneous nuclear Hs.524276 NM_005758 0.83 ribonucleoprotein A3 pseudogene 1 CDC42BPA 214464_at NM 003607, CDC42 binding protein Hs.35433 NM_003607 1.4 NM_014826 kinase alpha (DMPK-like) P15RS 218209_s_at NM_018170 hypothetical protein Hs.464912 NM_018170 0.79 FLJ10656 FLJ10534TSR 218156_s_at NM018128 TSR1, 20S rRNA Hs.388170 NM018128 0.75 1 accumulation, homolog (S. cerevisiae) RRM1 201476_s at NM_001033 ribonucleotide reductase Mi Hs.383396 A1692974 0.76 polypeptide USP4 202682_s_at NM_003363, ubiquitin specific peptidase 4 Hs.77500 NM_003363 1.2 NM_199443 (proto-oncogene) ZNF304 207753_at NM_020657 zinc finger protein 304 Hs.287374 NM_020657 1.3 CA2 209301_at NM_000067 carbonic anhydrase II Hs.155097 M36532 0.25 LOC92249 212957_s at hypothetical protein Hs.31532 AU154785 1.1 LOC92249 MARCH5 218582_at NM_017824 membrane-associatedring Hs.549165 NM_017824 0.81 finger (C3HC4) 5 TRMT5 221952_x_at NM_020810 TRM5 tRNA Hs.380159 AB037814 0.81 methyltransferase 5 homolog (S. cerevisiae) PRDX3 201619_at NM_006793, peroxiredoxin 3 Hs.523302 NM_006793 0.73 NM_014098 RAP1GDS1 217457_s at NM_021159 RAPI, GTP-GDP dissociation Hs.132858 X63465 0.82 Stimulator 1 20 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) NUMB 209073_s at NM_0010057 numb homolog (Drosophila) Hs.509909 AF015040 0.82 43,NM 00100 5744,NM_001 005745,NM_0 03744 KIF2 203087_s at NM_004520 kinesin heavy chain member Hs.533222 NM_004520 0.72 2 ACADSB 205355_at NM_001609 acyl-Coenzyme A Hs.81934 NM_001609 0.87 dehydrogenase, short/branched chain IBRDC3 213038_at NM_153341 IBR domain containing 3 Hs.546478 AL031602 0.88 TES 202719_s at NM_015641, testis derived transcript (3 Hs.533391 BC001451 1.3 I NM_152829 LIM domains) YDD19 37079_at YDD19 protein Hs.525826 U82319 0.92 GZMB 210164_at NM_004131 granzyme B (granzyme 2, Hs.1051 J03189 0.66 cytotoxic T-lymphocyte associated serine esterase 1) LAP3 217933_s at NM_015907 leucine aminopeptidase 3 Hs.479264 NM 015907 0.67 C17orf25 209092_s at NM_016080 chromosome 17 open reading Hs.279061 AF061730 0.72 frame 25 ZNF345 207236_at NM 003419 zinc finger protein 345 Hs.362324 NM 003419 1.1 KITLG 207029_at, NM_000899, KIT ligand Hs.1048 NM 000899, 0.75 211124_s at NM_003994 AF119835 CAMSAP1L1 212765_at NM203459 calmodulin regulated Hs.23585 AB029001 1.3 spectrin-associated protein 1 like 1 YTHDC2 205835_s at, NM_022828 YTH domain containing 2 Hs.231942 AW975818, 0.84 205836 s at NM022828 RABIF 204477at NM_002871 RAB interacting factor Hs.90875 U74324 1.2 SERBP1 217725_x at NM_0010180 SERPINE1 mRNA binding Hs.369448, NM_015640 0.81 67,NM__00101 protein 1 Hs.519284, 8068,NM_001 Hs.530412 018069,NM_0 15640 KPNB1 208975 s at NM002265 karyopherin (importin) beta 1 Hs.532793 L38951 0.74 BRIPI 221703_at NM 032043 BRCA1 interacting protein C- Hs.532799 AF360549 0.86 terminal helicase 1 IRF1 202531 at NM_002198 interferon regulatory factor 1 Hs.436061 NM_002198 0.62 TPIN 219258_at NM017858 TIMELESS interacting Hs.426696 NM_017858 0.73 protein SPFH1 202444 s at NM_006459 SPFH domain family, Hs.150087 NM_006459 0.76 member 1 SFPQ 201586 s at NM_005066 splicing factor Hs.355934 NM_005066 0.83 proline/glutamine-rich (polypyrimidine tract binding 21 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) protein associated) MGAT2 211061_s at NM_0010158 mannosyl (alpha-1,6-)- Hs.93338 BC006390 0.79 83,NM_00240 glycoprotein beta-1,2-N 8 acetylglucosaminyltransferase MCCC2 209624_s_at NM_022132 methylcrotonoyl-Coenzyme A Hs.167531 AB050049 0.6 carboxylase 2 (beta) DDAH2 215537_x at, NM_013974 dimethylarginine Hs.247362 AJ012008,A 1.2 214909_s at dimethylaminohydrolase 2 K026191 NP 201695_s at NM_000270 ' nucleoside phosphorylase Hs.75514 NM_000270 0.79 C]HEK1 205393_s_at, NM_001274 CHK1 checkpoint homolog Hs.24529 NM_001274 0.7 205394_at (S. pombe) MYOIB 212365_at NM_012223 myosin IB Hs.439620 BF215996 0.85 ATP5A1 213738 s at NM0010019 ATP synthase, H+ Hs.298280, A1587323 0.82 35,NM_00100 transporting, mitochondrial Hs.551998 1937,NM_004 F1 complex, alpha subunit, 046 isoform 1, cardiac muscle IL2RB 205291_at NM_000878 interleukin 2 receptor, beta Hs.474787 NM_000878 0.73 RPL39 217665_at NM_001000 ribosomal protein L39 Hs.558387 AA420614 1.3 (RPL39) CD59 212463_at NM_000611, CD59 antigen p18-20 (antigen Hs.278573 BE379006 1.5 NM_203329, identified by monoclonal NM_203330, antibodies 16.3A5, EJ16, NM_203331 EJ30, EL32 and G344) AMD1 201196_s at NM_0010330 adenosylmethionine Hs.159118 M21154 0.74 59,NM_00163 decarboxylase 1 4 GGA2 210658_s at NM_015044, golgi associated, gamma Hs.460336 BC000284 0.82 NM_138640 adaptin ear containing, ARF binding protein 2 MCM6 201930_at NM_005915 MCM6 minichromosome Hs.444118 NM_005915 0.75 maintenance deficient 6 (MISS homolog, S. pombe) (S. cerevisiae) SCC-1 12 213983_sat, NM015200 SCC-112 protein Hs.331431 AW991219, 0.8 212138_at AK021757 BCL7C 219072_at NM 004765 B-cell CLL/lymphoma 7C Hs.303197 NM 004765 1.2 HMGN2 208668_x_at NM_005517 high-mobility group Hs.181163 BC003689 0.9 nucleosomal binding domain 2 RBBP4 210371 _at, NM_005610 retinoblastoma binding Hs.555890 BC003092,X 0.8 217301 x at protein 4 71810 KIAA0090 212396 s at NM_015047 KIAA0090 Hs.439200 A1143233 0.81 SYNPO 202796 at NM_007286 synaptopodin Hs.435228 NM 007286 1.2 GPR161 214104_at NM_007369 Gprotein-coupledreceptor Hs.271809 A1703188 1.5 NM 153832 161 22 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) TMEM113 215509_s at NM_025222 transmembrane protein 113 Hs.194110 AL137654 0.72 SMC2L1 204240 s at NM_006444 SMC2 structural maintenance Hs.119023 NM_006444 0.65 of chromosomes 2-like 1 (yeast) CCNA2 203418_at NM_001237 cyclin A2 Hs.85137 NM_001237 0.6 VAPB 202549_at NM_004738 VAMP (vesicle-associated Hs.182625 AK025720 1.2 membrane protein)-associated protein B and C EXOSC9 213226_at NM_005033 exosome component 9 Hs.91728 A1346350 0.73 TRIM25 206911 at NM_005082 tripartite motif-containing 25 Hs.528952, NM_005082 0.88 Hs.551516 SCYL2 221220 s at NM 017988 SCYl-like 2 (S. cerevisiae) Hs.506481 NM_017988 0.85 RYK 214172_x at NM_0010058 RYK receptor-like tyrosine Hs.245869 BG032035 1.2 61,NM_00295 kinase 8 MTHFD1 202309_at NM_005956 methylenetetrahydrofolate Hs.435974 NM_005956 0.74 dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase RUNX1 211180_x_at NM0010018 runt-related transcription Hs.149261, D89788 1.1 90,NM_00175 factor 1 (acute myeloid Hs.278446 4 leukemia 1, aml1 oncogene) KPNA2 201088_at, NM_002266 karyopherin alpha 2 (RAG Hs.159557, NM002266, 0.77 211762_s at cohort 1, importin alpha 1) Hs.252712 BC005978 PSME1 200814_at NM_006263, proteasome (prosome, Hs.75348 NM006263 0.76 NM_176783 macropain) activator subunit 1 (PA28 alpha) TACC3 218308_at NM_006342 transforming, acidic coiled- Hs.104019 NM_006342 0.78 coil containing protein 3 FEN1 204768_s at NM_004111 flap structure-specific Hs.409065 NM 004111 0.73 endonuclease 1 GTF3C4 219198_at NM_012204 general transcription factor Hs.549088 NM012204 0.87 IC, polypeptide 4, 90kDa GEMIN4 217099_s at NM_015721 gem (nuclear organelle) Hs.499620 AF258545 0.76 associated protein 4 CTSS 202902_s at NM 004079 cathepsin S Hs.181301 NM_004079 0.74 MCM2 202107_s at NM_004526 MCM2 minichromosome Hs.477481 NM_004526 0.71 maintenance deficient 2, mitotin (S. cerevisiae) GPHN 220773_s at NM0010242 gephyrin Hs.208765 NM020806 0.67 18,NM 02080 23 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) 6 NUP50 218295_ s_at NM_007172, nucleoporin 50kDa Hs.475103 NM_007172 0.78 NM_153645, NM_153684 RANBP2L1 210676_x_at NM_005054, RAN binding protein 2-like 1 Hs.469630 U64675 0.83 NM_032260 NR5A2 208337_s_at NM_003822, nuclear receptor subfamily 5, Hs.33446 NM_003822 0.77 NM_205860 group A, member 2 PGD 201118_at NM_002631 phosphogluconate Hs.464071 NM_002631 0.75 dehydrogenase FUT4 209892_at,20 NM_002033 fucosyltransferase 4 (alpha Hs.390420 AF305083,M 0.78 9893_s_at (1,3) fucosyltransferase, 58596 myeloid-specific) RAB6A 201048_x at NM_002869, RAB6A, member RAS Hs.503222, NM_002869 0.81 NM_198896 oncogene family Hs.535586 CCNT2 204645_at NM_001241, cyclin T2 Hs.292754 NM 001241 0.87 NM_058241 TFRC 207332s_at NM_003234 transferrin receptor (p90, Hs.529618 NM 003234 0.63 CD71) BIRC5 202095_s at NM_0010122 baculoviral AP repeat- Hs.514527 NM_001168 0.7 70,NM_00101 containing 5 (survivin) 2271,NM_001 168 PGGT1B 206288_at NM_005023 protein Hs.254006 NM_005023 0.8 geranylgeranyltransferase type I, beta subunit USP14 201672_s_at NM_005151 ubiquitin specific peptidase Hs.464416 NM_005151 0.81 14 (tRNA-guanine transglycosylase) PURA 204020_at NM_005859 purine-rich element binding Hs.443121 BF739943 1.2 protein A LMAN1 203293 s at, NM_005570 lectin, mannose-binding, 1 Hs.465295 NM 005570, 0.82 203294_s_at U09716 WDR45L 209076_s at NM_019613 WDR45-like Hs.201390 BC000974 0.82 SGCD 213543_at NM000337, sarcoglycan, delta (35kDa Hs.387207 AA570453 1.2 NM_172244 dystrophin-associated glycoprotein) LRP8 205282_at NM_0010180 low density lipoprotein Hs.444637 NM_004631 0.78 54,NM_00463 receptor-related protein 8, 1, apolipoprotein e receptor NM_017522, NM_033300 ITGA4 205885_s at NM_000885 integrin, alpha 4 (antigen Hs.555880 L12002 0.74 CD49D, alpha 4 subunit of VLA-4 receptor) 24 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) BUB3 201458_s_at NM_0010077 BUB3 budding uninhibited by Hs.418533 NM_004725 0.79 93,NM_00472 benzimidazoles 3 homolog 5 (yeast) KIF18A 221258_s at NM_031217 kinesin family member 18A Hs.301052 NM_031217 0.83 FKBP9 212169_at NM_007270 FK506 binding protein 9, 63 Hs.103934 AL050187 1.2 kDa ATF6 217550_at NM_007348 activating transcription factor Hs.492740 AA576497 1.4 6 TNFRSF11A 207037_at NM_003839 tumor necrosis factor receptor Hs.204044 NM_003839 0.68 superfamily, member 11 a, NFKB activator KIAA0841 213054 at KIAA0841 Hs.7426 AA845355 0.9 TGFB2 209909_s_at NM_003238 transforming growth factor, Hs.133379 M19154 1.1 beta 2 ITGB5 201125s_ at, NM 002213 integrin, beta 5 Hs.13155 NM_002213, 1.2 201124_at, AL048423,A 214021_x at 1335208 RABGEF1 218310_at NM_014504 RAB guanine nucleotide Hs.530053 NM014504 1.2 exchange factor (GEF) 1 PBX1 205253_at,21 NM_002585 pre-B-cell leukemia Hs.493096 NM_002585, 1.2 2148_at transcription factor 1 AL049381 ZNF148 203318 s at NM 021964 zinc finger protein 148 (pHZ- Hs.380334 NM_021964 1.2 52) ZWINT 204026 s at NM_0010054 ZW10 interactor Hs.42650 NM_007057 0.66 13,NM_00100 5414,NM007 057, NM_032997 ZDHHC3 213675_at NM_016598 zinc finger, DHHC-type Hs.61430 W61005 1.3 containing 3 CDCA8 221520_sat NM_018101 cell division cycle associated Hs.524571 BC001651 0.76 8 CUTLI 214743_at NM_001913, cut-like 1, CCAAT Hs.438974 BE046521 1.3 NM_181500, displacement protein NM_181552 (Drosophila) C18orf9 219311_at NM024899 chromosome 18 open reading Hs.236940 NM024899 0.73 frame 9 TXNDC 209476_at NM_030755 thioredoxin domain Hs.125221 AL080080 0.75 containing POLE2 205909_at NM_002692 polymerase (DNA directed), Hs.162777 NM_002692 0.73 epsilon 2 (p59 subunit) SPCS3 218817_at NM021928 signal peptidase complex Hs.42194 NM_021928 0.7 subunit 3 homolog (S. cerevisiae) CANDI 208839_s at NM_018448 cullin-associated and Hs.546407 AL136810 0.84 25 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) neddylation-dissociated 1 U2AF2 218381_s_at NM 0010124 U2 (RNU2) small nuclear Hs.528007 NM_007279 0.83 78,NM_00727 RNA auxiliary factor 2 9 WDHD1 204728_s_at NM_0010083 WD repeat and HMG-box Hs.385998 NM_007086 0.73 96,NM_00708 DNA binding protein 1 6 HEMI 209734_at NM_005337 hematopoietic protein 1 Hs.182014 BC001604 0.9 RABEP1 214552 s at NM_004703 rabaptin, RAB GTPase Hs.551518 AF098638 0.84 binding effector protein 1 SYDE1 44702_at NM_033025 synapse defective 1, Rho Hs.528701 R77097 1.1 GTPase, homolog 1 (C. elegans) WFDC1 219478_at NM_021197 WAP four-disulfide core Hs.36688 NM 021197 1.2 domain 1 TBX2 40560_at NM 005994 T-box 2 Hs.531085 U28049 1.1 GART 210005_at NM_000819, phosphoribosylglycinamide Hs.473648 D32051 0.84 NM 175085 formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazol e synthetase H2AFZ 213911_s at, NM_002106 H2A histone family, member Hs.119192 BF718636, 0.8 200853_at Z NM_ 002106 CD7 214551_sat NM_006137 CD7 antigen (p41) Hs.36972 NM_006137 0.8 ELOVL6 210868 s at NM_024090 ELOVL family member 6, Hs.412939 BC001305 0.81 elongation of long chain fatty acids (FEN1/Elo2, SUR4/Elo3-like, yeast) CACNB3 34726_at NM_000725 calcium channel, voltage- Hs.250712 U07139 1.2 dependent, beta 3 subunit TAPI 202307 s at NM 000593 transporter 1, ATP-binding Hs.352018 NM_000593 0.68 cassette, sub-family B (MDR/TAP) NUP98 210793_s at NM_005387, nucleoporin 98kDa Hs.524750 U41815 0.75 NM_016320, NM_139131, NM_139132 CHAF1A 214426_xat, NM_005483 chromatin assembly factor 1, Hs.79018 BF062223, 0.83 203976 s at subunit A (p150) NM_005483 EPAS1 200878_at NM_001430 endothelial PAS domain Hs.468410 AF052094 1.3 protein 1 RNGTT 204207_s at NM_003800 RNA guanylyltransferase and Hs. 127219 ABO12142 0.8 5'-phosphatase 26 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) KLF7 204334_at NM_003709 Kruppel-like factor 7 Hs.471221 AA488672 1.1 (ubiquitous) C4orfl6 219023_at NM_018569 chromosome 4 open reading Hs.435991 NM_018569 0.77 frame 16 YBX2 219704_at NM 015982 Y box binding protein 2 Hs.380691 NM_015982 0.75 IVD 216958_s.at NM_002225 isovaleryl Coenzyme A Hs.513646 AK022777 0.81 dehydrogenase PEG3 209242_at NM_006210 paternally expressed 3 Hs.201776 AL042588 1.2 FBXL14 213145_at NM 152441 F-box and leucine-rich repeat Hs.367956 BF001666 0.83 protein 14 TMEPAI 217875 s at NM_020182, transmembrane, prostate Hs.517155 NM_020182 1.4 NM_199169, androgen induced RNA NM 199170, NM_199171 RNF138' 218738_s_at NM_016271, ring finger protein 138 Hs.302408, NM016271 0.82 NM_198128 Hs.501040 DNM1L 203105_s at NM_005690, dynamin 1-like Hs.550499 NM012062 0.87 NM_012062, NM_012063 LHCGR 215306_at NM_000233 luteinizing Hs.468490 AL049443 -1.3 hormone/choriogonadotropin receptor SOCS6 214462 at, NM_004232 suppressor of cytokine Hs.591068 NM_004232, 0.85 206020_at signaling 6 (SOCS6) NM_016387 CEP350 213956_at NM_014810 centrosomal protein 350kDa Hs.413045 AW299294 1.3 PTGER3 210374 xat, NM_000957, prostaglandin E receptor 3 Hs.445000 D38300, 1.1 210831s at NM_198712, (subtype EP3) L27489 NM_198713, NM198714, NM_198715, NM_198716, NM_198717, NM_198718, NM_198719, NM198720 M11S1 200723 s at NM005898, membrane component, Hs.471818 NM005898 0.9 NM203364 chromosome 11, surface marker 1 RFC5 203210_s_at NM_007370, replication factor C (activator Hs.506989 NM_007370 0.79 NM_181578 1) 5,36.5kDa INDO 210029_at NM_002164 indoleamine-pyrrole 2,3 Hs.840 M34455 0.74 dioxygenase KIAA0286 212619_at NM_015257 NA Hs.533787 AW205215 0.77 MOBKlB 201298_s at NM018221 MOB1, Mps One Binder Hs.196437 BC003398 0.84 kinase activator-like 1B (yeast) 27 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) FLJ20273 218035_s at NM_019027 RNA-binding protein Hs.518727 NM_019027 0.73 HADHSC 211569_s_at NM_005327 L-3-hydroxyacyl-Coenzyme Hs.438289 AF001903 0.62 A dehydrogenase, short chain SSPN 204964 s at NM_005086 sarcospan (Kras oncogene- Hs.183428 NM_005086 L6 associated gene) AP2B1 200615_s at NM_0010300 adaptor-related protein Hs.514819 AL567295 0.77 06,NM_00128 complex 2, beta 1 subunit 2 EIF4A1 201530_x at, NM 001416 eukaryotic translation Hs.129673 NM_001416 0.79 214805 at initiation factor 4A, isoform 1 U79273 DEPDC1 220295 x at NM 017779 DEP domain containing 1 Hs.445098 NM_017779 0.66 AGPAT5 218096_at NM_018361 1-acylglycerol-3-phosphate Hs.490899 NM_018361 0.68 O-acyltransferase 5 (lysophosphatidic acid acyltransferase, epsilon) HNRPDL 201993_x_at NM_005463, heterogeneous nuclear Hs.527105 NM_005463 0.86 NM_031372 ribonucleoprotein D-like GBP1 202270_at NM_002053 guanylate binding protein 1, Hs.62661, NM_002053 0.61 interferon-inducible, 67kDa Hs.443527 AMIGO2 222108_at NM_181847 adhesion molecule with Ig- Hs.121520 AC004010 1.6 like domain 2 XPO7 208459_s at NM 015024 exportin 7 Hs.172685 NM_015024 0.78 PAWR 204005_s at NM_002583 PRKC, apoptosis, WT1, Hs.406074 NM_002583 0.71 regulator NARS 200027_at NM 004539 asparaginyl-tRNA synthetase Hs.465224 NM_004539 0.84 CENPA 204962 s at NM_001809 centromere protein A, l7kDa Hs.1594 NM_001809 0.69 KIF15 219306at NM 020242 kinesin family member 15 Hs.307529 NM_020242 0.78 ZNF518 204291 at NM 014803 zinc finger protein 518 Hs.147895 NM_014803 0.88 LPP 202821_s at NM005578 LIM domain containing Hs.444362 AL044018 1.3 preferred translocation partner in lipoma BRRN1 212949_at NM_015341 barren homolog (Drosophila) Hs.308045 D38553 0.76 C5orf4 48031 r at NM_016348, chromosome 5 open reading Hs.519694 H93077 1.2 NM_032385 frame 4 UBAPI 46270_at NM_016525 ubiquitin associated protein I Hs.268963 AL039447 1.1 SH3GLB1 209090_s at NM_016009 S113-domain GRB2-like Hs.136309 AL049597 1.2 endophilin B 1 CDKN1C 213182_x_at NM_000076 cyclin-dependent kinase Hs.106070 R78668 1.4 inhibitor IC (p57, Kip2) MCM10 220651 s at NM_018518, MCM10 minichromosome Hs.198363 NM_018518 0.74 NM_182751 maintenance deficient 10 (S. cerevisiae) KIAA0265 209254 at NM_014997 KIAA0265 protein Hs.520710 A1808625 1.2 28 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) BUB1 209642_at NM_004336 BUBI budding uninhibited by Hs.469649 AF043294 0.68 benzimidazoles 1 homolog (yeast) LGALS3BP 200923_at NM_005567 lectin, galactoside-binding, Hs.514535 NM_005567 0.8 soluble, 3 binding protein NCAPD2 201774_s at NM_014865 non-SMC condensin I Hs.5719 AK022511 0.73 complex, subunit D2 CD86 205686 s at NM 006889, CD86 antigen (CD28 antigen Hs.171182 NM_006889 0.88 NM_175862 ligand 2, B7-2 antigen) Cl6orf30 219315_s at NM_024600 chromosome 16 open reading Hs.459652 NM_024600 1.2 frame 30 RBBP8 203344_s_at NM_002894, retinoblastoma binding Hs.546282 NM 002894 0.79 NM_203291, protein 8 NM 203292 FEMIC 213341_at NM_020177 fem-1 homolog c (C.elegans) Hs.47367 AI862658 0.82 NUP160 214962 s at NM 015231 nucleoporin 160kDa Hs.372099 AK026236 0.84 VAMP4 213480_at NM_003762, vesicle-associated membrane Hs.6651 AF052100 1.1 NM_201994 protein 4 C9orf76 218979_at NM 024945 chromosome 9 open reading Hs.284137 NM_024945 0.8 frame 76 DHX15 201386_s at NM_001358 DEAH (Asp-Glu-Ala-His) Hs.5683 AF279891 0.83 box polypeptide 15 RIG 221127_s at regulated in glioma Hs.292156 NM_006394 1.2 HBP1 209102_s at NM_012257 HMG-box transcription factor Hs.162032 AF019214 1.2 1 ABCE1 201873_s_at, NM_002940 ATP-binding cassette, sub- Hs.12013 NM_002940, 0.79 201872 s at family E (OABP), member 1 A1002002 PPA2 220741_s at NM_006903, pyrophosphatase (inorganic) 2 Hs.480452 NM_006903 0.81 NM_176866, NM_176867, NM_176869 CPD 201942_s_at NM_001304 carboxypeptidase D Hs.446079 D85390 0.68 KIAA0828 215672 s at NM 015328 adenosylhomocysteinase 3 Hs.195058 AK025372 0.73 K-ALPHA-i 211058_x_at NM_006082 alpha tubulin Hs.524390 BC006379 0.85 RNMT 202684_s_at NM_003799 RNA (guanine-7-) Hs.8086 AB020966 0.9 methyltransferase MIS12 221559_s_at NM_024039 MIS12 homolog (yeast) Hs.267194 BC000229 0.8 AURKB 209464_at NM_004217 aurora kinase B Hs.442658 AB011446 0.71 FAM64A 221591_s_at NM_019013 family with sequence Hs.404323 BC005004 0.8 similarity 64, member A TAP2 204770_at NM_000544, transporter 2, ATP-binding Hs.502 NM_000544 0.82 NM 018833 cassette, sub-family B (MDR/TAP) 29 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) PCDHGC3 205717_x at NM_002588, protocadherin gamma Hs.368160 NM_002588 1.2 NM_032402, subfamily C, 3 NM_032403 AVEN 219366_at NM_020371 apoptosis, caspase activation Hs.555966 NM_020371 1.1 inhibitor HMGB2 208808 s at NM 002129 high-mobility group box 2 Hs.434953 BC000903 0.76 CDC2 203214_x_at NM_001786, cell division cycle 2, GI to S Hs.334562 NM_001786 0.72 NM_033379 and G2 to M RIF1 214700_x_at NM_018151 RAP1 interacting factor Hs.536537 AK000323 0.84 homolog (yeast) TCF7L2 216511_s_at NM_030756 transcription factor 7-like 2 Hs.501080 AJ270770 0.8 (T-cell specific, HMG-box) KIF1 1 204444_at NM_004523 kinesin family member 11 Hs.8878 NM_004523 0.68 TTC19 217964_at NM_017775 tetratricopeptide repeat Hs.462316 NM_017775 0.67 domain 19 MDSO32 221706 s at NM_018467 uncharacterized Hs.16187 BC006005 1.2 hematopoietic stem/progenitor cells protein MDS032 PSMA3 201532_at NM_002788, proteasome (prosome, Hs.531089 NM_002788 0.76 NM_152132 macropain) subunit, alpha type, 3 PDGFA 205463_s_at platelet-derived growth factor Hs.376032, NM_002607 1.3 alpha polypeptide Hs.521331 GTF2H2 221540_x_at NM_001515 general transcription factor Hs.191356, AF078847 0.86 IH, polypeptide 2, 44kDa Hs.398348 CXCL13 205242_at NM_006419 chemokine (C-X-C motif) Hs.100431 NM_006419 0.36 ligand 13 (B-cell chemoattractant) FOXM1 202580_xat NM_021953, forkhead box M1 Hs.239 NM_021953 0.7 NM_202002, NM_202003 YARS 212048_s at NM 003680 tyrosyl-tRNA synthetase Hs.213264 AW245400 0.87 SE57-1 220180_at NM_025214 coiled-coil domain containing Hs.120790 NM_025214 0.77 68 CLCA4 220026_at NM_012128 chloride channel, calcium Hs.546343 NM_012128 0.64 activated, family member 4 MCAM 211340 s at NM_006500 melanoma cell adhesion Hs.511397 M28882 1.2 molecule PBXIP1 214177_s_at NM_020524 pre-B-cell leukemia Hs.505806 A1935162 1.2 transcription factor interacting protein 1 PPMID 204566_at NM_003620 protein phosphatase 1D IHs.286073 NM_003620 0.88 30 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Gene Description Unigene Other Expressio Probe IDs Access. Access. Genbank n Fold Access. Difference (relapse/ non relapse) magnesium-dependent, delta isoform FLJ22471 218175 at NM_025140 NA Hs.114111 NM_025140 1.2 ZBTB20 205383_s at NM_015642 zinc finger and BTB domain Hs.122417 NM_015642 1.4 containing 20 RRM2 209773_s_at NM_001034 ribonucleotide reductase M2 H1s.226390 BC001886 0.69 polypeptide Table 2: Markers with expression correlating to that of the 22 genes from NZ signature. 5 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) CCL5 1405_iLat, NM 002985 chemokine (C-C motif) ligand Hs.514821 M21121, 0.69 204655_at 5 NM_002985 SFRS1O 200893_at NM_004593 splicing factor, Hs.533122 NM_004593 0.96 arginine/serine-rich 10 (transformer 2 homolog, Drosophila) HLA-E 200904_at NM 005516 major histocompatibility Hs.381008 X56841 1 complex, class I, E K-ALPHA-1 201090_x_at NM_006082 alpha tubulin Hs.524390 NM006082 0.87 PSMA5 201274_at NM002790 proteasome (prosome, Hs.485246 NM_002790 0.95 macropain) subunit, alpha type, 5 TOP2A 201292_at NM_001067 topoisomerase (DNA) II alpha Hs.156346 AL561834 0.77 170kDa EBNA1BP2 201323_at NM_006824 EBNA1 binding protein 2 Hs.346868 NM_006824 0.98 SNRPC 201342_at NM_003093 small nuclear Hs.1063 NM_003093 1 ribonucleoprotein polypeptide C UBE2L6 201649_at NM 004223, ubiquitin-conjugating enzyme Hs.425777 NM_004223 0.75 NM 198183 E2L 6 LAPTM5 201720_s at NM_006762 lysosomal associated Hs.371021 A1589086 0.89 multispanning membrane protein 5 CTSL 202087 s at NM_001912, cathepsinL Hs.418123 NM_001912 0.97 31 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) NM_145918 GBP1 202269_x_at NM_002053 guanylate binding protein 1, Hs.62661, BC002666 0.69 interferon-inducible, 67kDa Hs.443527 TNFAIP2 202510_s at NM_006291 tumor necrosis factor, alpha- Hs.525607 NM_006291 0.91 induced protein 2 CCNB2 202705 at NM 004701 cyclin B2 Hs.194698 NM_004701 0.83 GBP2 202748_at NM_004120 guanylate binding protein 2, Hs.386567 NM_004120 0.87 interferon-inducible CDC20 202870_s_at NM_001255 CDC20 cell division cycle 20 Hs.524947 NM_001255 0.78 homolog (S. cerevisiae) HATI 203138_at NM_0010330 histone acetyltransferase 1 Hs.470611 NM_003642 0.95 85,NM_00364 2 SPAG5 203145 at NM_006461 sperm associated antigen 5 Hs.514033 NM 006461 0.87 RFC5 203209_at NM_007370, replication factor C (activator Hs.506989 BC001866 0.79 NM_181578 1) 5, 36.5kDa MYCBP 203360 s at NM 012333 c-myc binding protein Hs.370040 D50692 1 BUBIB 203755_at NM_001211 BUB1 budding uninhibited by Hs.36708 NM_001211 0.85 benzimidazoles 1 homolog beta (yeast) SLA 203761_at NM_006748 Src-like-adaptor Hs.75367 NM_006748 0.97 VRKI 203856_at NM_003384 vaccinia related kinase 1 Hs.422662 NM_003384 0.72 PIK3CD 203879_at NM_005026 phosphoinositide-3-kinase, Hs.518451 U86453 0.99 catalytic, delta polypeptide HLA-DMB 203932_at NM_002118 major histocompatibility Hs.1162 NM_002118 0.82 complex, class II, DM beta TRIP13 204033_at NM_004237 thyroid hormone receptor Hs.436187 NM_004237 0.78 interactor 13 RARRES3 204070_at NM_004585 retinoic acid receptor Hs. 17466 NM_004585 0.96 responder (tazarotene induced) 3 CKS2 204170 s at NM_001827 CDC28 protein kinase Hs.83758 NM_001827 0.8 regulatory subunit 2 APOBEC3G 204205_at NM_021822 apolipoprotein B mRNA Hs.474853 NM_021822 0.74 editing enzyme, catalytic polypeptide-like 3G PSMB9 204279_at NM_002800, proteasome (prosome, Hs.381081 NM_002800 0.63 NM_148954 macropain) subunit, beta type, 9 (large multifunctional peptidase 2) FUSIPI 204299_at NM_054016 FUS interacting protein Hs.3530 NM 021993 0.9 (serine/arginine-rich) 1 SELL 204563_at NM 000655 selectin L (lymphocyte Hs.82848 NM 000655 0.88 32 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description IJnigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) adhesion molecule 1) DKK1 204602_at NM_012242 dickkopfhomolog 1 Hs.40499 NM_012242 0.95 (Xenopus laevis) KIF23 204709_s_at NM_004856, kinesin family member 23 Hs.270845 NM_004856 0.9 NM_138555 TTK 204822_at NM_003318 TTK protein kinase Hs.169840 NM_003318 0.8 ECGF1 204858_s at NM_001953 endothelial cell growth factor Hs.546251 NM_001953 0.85 1 (platelet-derived) LCP2 205269_at, NM_005565 lymphocyte cytosolic protein Hs.304475 A1123251,N 0.91 205270_s at 2 (SH2 domain containing M_005565 leukocyte protein of 76kDa) BTN2A2 205298_s_at NM_006995, butyrophilin, subfamily 2, Hs.373938 W58757 0.94 NM_181531 member A2 BMP5 205431 s-at NM_021073 bone morphogenetic protein 5 Hs.296648 NM_021073 0.9 GZMA 205488_at NM_006144 granzyme A (granzyme 1, Hs.90708 NM 006144 0.68 cytotoxic T-lymphocyte associated serine esterase 3) SMURF2 205596 s at NM_022739 SMAD specific E3 ubiquitin Hs.515011 AY014180 1 protein ligase 2 CD8A 205758_at NM 001768, CD8 antigen, alpha Hs.85258 AW006735 0.78 NM_171827 polypeptide (p32) CD2 205831_at NM_001767 CD2 antigen (p50), sheep red Hs.523500 NM_001767 0.87 blood cell receptor JAK2 205842 s at NM_004972 Janus kinase 2 (a protein Hs.434374 AF001362 0.86 tyrosine kinase) UBD 205890 s at NM_006398 ubiquitin D Hs.44532 NM_006398 0.41 ADH1C 206262_at NM_000669 alcohol dehydrogenase 1C Hs.2523 NM_000669 0.33 (class I), gamma polypeptide AIM2 206513_at NM 004833 absent in melanoma 2 Hs.281898 NM_004833 0.91 SI 206664_at NM_001041 sucrase-isomaltase (alpha- Hs.429596 NM_001041 0.39 glucosidase) NAT2 206797_at NM_000015 N-acetyltransferase 2 Hs.2 NM_000015 0.82 (arylamine N acetyltransferase) SP110 208012_x_at NM_004509, SP1 10 nuclear body protein Hs.145150 NM_004509 0.95 NM_004510, NM_080424 PRDX1 208680at NM_002574, peroxiredoxin 1 Hs.180909 L19184 1 NM_181696, NM 181697 PSMA6 208805_at NM_002791 proteasome (prosome, Hs.446260 BC002979 0.87 macropain) subunit, alpha type, 6 33 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) IF116 208966_x at NM_005531 interferon, gamma-inducible Hs.380250 AF208043 1.2 protein 16 PPIG 208995 s at NM_004792 peptidyl-prolyl isomerase G Hs.470544 U40763 0.98 (cyclophilin G) KIF2C 209408_at, NM 006845 kinesin family member 2C Hs.69360 U63743, 0.75 211519_s at AY026505 APOL1 209546_s_at NM_003661, apolipoprotein L, 1 Hs. 114309 AF323540 0.98 NM_145343, NM_145344 CD74 209619_at NM 0010251 CD74 antigen (invariant Hs.436568 K01144 0.76 58,NM_ 00102 polypeptide of major 5159,NM_004 histocompatibility complex, 355 class II antigen-associated) HMNR 209709_s_at NM_012484, hyaluronan-mediated motility Hs.72550 U29343 0.84 NM_012485 receptor (RHAMM) CDKN3 209714_sat NM_005192 cyclin-dependent kinase Hs.84113 AF213033 0.71 inhibitor 3 (CDK2-associated dual specificity phosphatase) BUB3 209974_s_at NM_0010077 BUB3 budding uninhibited by Hs.418533 AF047473 0.84 93,NM_00472 benzimidazoles 3 homolog 5 (yeast) SOCS1 210001_s at NM_003745 suppressor of cytokine Hs.50640 AB005043 0.93 signaling 1 CD3Z 210031_at NM_000734, CD3Z antigen, zeta Hs.156445 J04132 0.87 NM_198053 polypeptide (TiT3 complex) CACYBP 210691_s at NM_0010072 calcyclin binding protein Hs.508524 AF275803 0.97 14,NM_01441 2 HLA-DRA 210982_s at NM_019111 major histocompatibility Hs.520048 M60333 0.74 complex, class II, DR alpha NEK2 211080_s at NM_002497 NIMA (never in mitosis gene Hs.153704 Z25425 0.77 a)-related kinase 2 NF2 211091_s_at NM_000268, neurofibromin 2 (bilateral Hs.187898 AF122828 0.96 NM_016418, acoustic neuroma) NM_181825, NM_181826, NM_181827, NM_181828, NM_181829, NM_181830, NM_181831, NM_181832, NM_181833, NM_181834, NM_181835 FYB 211795s at NM 001465, FYN binding protein (FYB- Hs.370503 AF198052 0.83 NM_199335 120/130) 34 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) HLA-DPAl 211991_s at NM_033554 major histocompatibility Hs.347270 M27487 0.75 complex, class II, DP alpha 1 PTPRC 212587sat, NM_002838, protein tyrosine phosphatase, Hs.192039 A1809341,Y 0.77 212588_at NM_080921, receptor type, C 00062 NM_080922, NM_080923 SP3 213168_at NM_0010173 Sp3 transcription factor Hs.531587 AU145005 0.98 71,NM_00311 1 ITGAL 213475sat NM_002209 integrin, alpha L (antigen Hs.174103 AC002310 0.85 CD11A (p180), lymphocyte function-associated antigen 1, alpha polypeptide) RAC2 213603_s at NM_002872 ras-related C3 botulinum Hs.517601 BE138888 0.92 toxin substrate 2 (rho family, small GTP binding protein Rac2) DNA2L 213647_at DNA2 DNA replication Hs.532446 D42046 0.87 helicase 2-like (yeast) TRAF3IP3 213888_s at NM_025228 TRAF3 interacting protein 3 Hs.147434 AL022398 0.86 NKG7 213915_at NM005601 natural killer cell group 7 Hs.10306 NM_005601 0.72 sequence SFRS7 214141_x_at NM0010316 splicing factor, Hs.309090 BF033354 0.88 84,NM_00627 arginine/serine-rich 7, 35kDa 6 ZG16 214142_at NM152338 zymogen granule protein 16 Hs.184507 A1732905 0.18 PRF1 214617_at NM005041 perforin 1 (pore forming Hs.2200 A1445650 0.81 protein) CCNB1 214710 s at NM031966 cyclin BI Hs.23960 BE407516 0.63 KIAA0907 214995 s at NM_014949 KIAA0907 Hs.24656 BF508948 0.82 GTSE1 215942_s_at NM_016426 G-2 and S-phase expressed 1 Hs.386189, BF973178 0.86 Hs.475140 HMGB3 216548 x _at NM005342 high-mobility group box 3 Hs.19114 AL049709 0.97 HLA-DMA 217478_s_at NM_006120 major histocompatibility Hs.351279 X76775 0.8 complex, class II, DM alpha C20orf45 217851_s_at NM016045 chromosome 20 open reading Hs.3945 NM_016045 1.1 frame 45 MRPL42 217919 sat NM_014050, mitochondrialribosomal Hs.199579 BE782148 0.79 NM_172177, protein L42 NM_172178 NUSAP1 218039_at, NM_016359, nucleolar and spindle Hs.511093 NM_016359, 0.92 219978 s at NM018454 associated protein 1 NM_018454 TMEM48 218073 s at NM018087 transmembrane protein 48 Hs.476525 NM_018087 0.71 35 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) DHX40 218277_s_at NM_024612 DEAH (Asp-Glu-Ala-His) Hs.29403 NM_024612 1.1 box polypeptide 40 NFSI 218455_at NM_021100, NFS1 nitrogen fixation 1 (S. Hs.194692 NM_021100 1 NM_181679 cerevisiae) Cl0orf3 218542_at NM018131 chromosome 10 open reading Hs.14559 NM018131 0.77 frame 3 NCAPG 218663_at NM_022346 non-SMC condensin I Hs.446201, NM_022346 0.73 complex, subunit G Hs.479270 FBXO5 218875 sat NM 012177 F-box protein 5 Hs.520506 NM 012177 0.89 SLAMF8 219385_at NM_020125 SLAM family member 8 Hs.438683 NM_020125 0.94 CENPN 219555 s at NM 018455 centromere proteinN Hs.283532 NM_018455 0.81 ATP13A3 219558 at ATPase type 13A3 Hs.529609 NM_024524 0.75 ECT2 219787 s at NM 018098 epithelial cell transforming Hs.518299 NM_018098 0.75 sequence 2 oncogene ASPM 219918_s at NM_018136 asp (abnormal spindle)-like, Hs.121028 NM_018123 0.89 microcephaly associated (Drosophila) ZC3HAV1 220104_at NM_020119, zinc finger CCCH-type, Hs.133512 NM_020119 0.93 NM_024625 antiviral 1 CLEC2D 220132 s at NM_0010044 C-type lectin superfamily 2, Hs.268326 NM 013269 0.91 19,NM 00100 member D 4420,NM_013 269 MS4A12 220834_at NM_017716 membrane-spanning 4- Hs.272789 NM 017716 0.5 domains, subfamily A, member 12 Clorffl12 220840 s at NM_018186 chromosome 1 open reading Hs.443551 NM_018186 0.96 frame 112 TPRT 220865_s at NM_014317 trans-prenyltransferase Hs.555924 NM014317 0.92 APOL3 221087_s at NM_014349, apolipoprotein L, 3 Hs.474737 NM_014349 0.84 NM_030644, NM_145639, NM_145640, NM_145641, NM_145642 Cl4orfl56 221434_s at NM_031210 chromosome 14 open reading Hs.324521 NM_031210 0.9 frame 156 YTHDF3 221749_at NM_152758 YTH domain family, member Hs.491861 AU157915 0.95 3 LOC146909 222039_at hypothetical protein Hs.135094 AA292789 0.83 LOC146909 TRAFD1 35254_at NM 006700 TRAF-type zinc finger Hs.5148 AB007447 0.98 36 WO 2007/073220 PCT/NZ2006/000343 Gene Symbol Affymetrix Refseq Access Gene Description Unigene Genbank Expression Probe IDs Access Access Fold Difference (relapse/ non relapse) domain containing 1 ESPLI 38158_at NM_012291 extra spindle poles like 1 (S. Hs.153479 D79987 0.87 cerevisiae) BTN3A3 38241_at NM_006994, butyrophilin, subfamily 3, Hs.167741 U90548 0.9 NM 197974 member A3 General approaches to prognostic marker detection The following approaches are non-limiting methods that can be used to detect the proliferation markers, including CCPM family members: microarray approaches 5 using oligonucleotide probes selective for a CCPM; real-time qPCR on tumour samples using CCPM specific primers and probes; real-time qPCR on lymph node, blood, serum, faecal, or urine samples using CCPM specific primers and probes; enzyme-linked immunological assays (ELISA); immunohistochemistry using anti marker antibodies; and analysis of array or qPCR data using computers. 10 Other useful methods include northern blotting and in situ hybridization (Parker and Barnes, Methods in Molecular Biology 106: 247-283 (1999)); RNase protection assays (Hod, BioTechniques 13: 852-854 (1992)); reverse transcription polymerase chain reaction (RT-PCR; Weis et al., Trends in Genetics 8: 263-264 15 (1992)); serial analysis of gene expression (SAGE; Velculescu et al., Science 270: 484-487 (1995); and Velculescu et al., Cell 88: 243-51 (1997)), MassARRAY technology (Sequenom, San Diego, CA), and gene expression analysis by massively parallel signature sequencing (MPSS; Brenner et al., Nature Biotechnology 18: 630 634 (2000)). Alternatively, antibodies may be employed that can recognize specific 20 complexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-polypeptide duplexes. Primary data can be collected and fold change analysis can be performed, for example, by comparison of marker expression levels in tumour tissue and non-tumour 25 tissue; by comparison of marker expression levels to levels determined in recurring tumours and non-recurring tumours; by comparison of marker expression levels to levels determined in tumours with or without metastasis; by comparison of marker 37 WO 2007/073220 PCT/NZ2006/000343 expression levels to levels determined in differently staged tumours; or by comparison of marker expression levels to levels determined in cells with different levels of proliferation. A negative or positive prognosis is determined based on this analysis. Further analysis of tumour marker expression includes matching those markers 5 exhibiting increased or decreased expression with expression profiles of known colorectal tumours to provide a prognosis. A threshold for concluding that expression is increased will be dependent on the particular marker and also the particular predictive model that is to be applied. The 10 threshold is generally set to achieve the highest sensitivity and selectivity with the lowest error rate, although variations may be desirable for a particular clinical situation. The desired threshold is determined by analysing a population of sufficient size taking into account the statistical variability of any predictive model and is calculated from the size of the sample used to produce the predictive model. The 15 same applies for the determination of a threshold for concluding that expression is decreased. It can be appreciated that other thresholds, or methods for establishing a threshold,for concluding that increased or decreased expression has occurred can be selected without departing from the scope of this invention. 20 It is also possible that a prediction model may produce as it's output a numerical value, for example a score, likelihood value or probability. In these instances, it is possible to apply thresholds to the results produced by prediction models, and in these cases similar principles apply as those used to set thresholds for expression values. 25 Once the expression level, or output of a prediction model, of a predictive signature in a tumour sample has been obtained, the likelihood of the cancer recurring can then be determined. From the markers identified, prognostic signatures comprising one or more 30 CCPMs can be used to determine the prognosis of a cancer, by comparing the expression level of the one or more markers to the disclosed prognostic signature. By comparing the expression of one or more of the CCPMs in a tumour sample with the disclosed prognostic signature, the likelihood of the cancer recurring can be determined. The comparison of expression levels of the prognostic signature to 38 WO 2007/073220 PCT/NZ2006/000343 establish a prognosis can be done by applying a predictive model as described previously. Determining the likelihood of the cancer recurring is of great value to the 5 medical practitioner. A high likelihood of re-occurrence means that a longer or higher dose treatment should be given, and the patient should be more closely monitored for signs of recurrence of the cancer. An accurate prognosis is also of benefit to the patient. It allows the patient, along with their partners, family, and friends to also make decisions about treatment, as well as decisions about their future and lifestyle 10 changes. Therefore, the invention also provides for a method establishing a treatment regime for a particular cancer based on the prognosis established by matching the expression of the markers in a tumour sample with the differential expression signature. 15 It will be appreciated that the marker selection, or construction of a prognostic signature, does not have to be restricted to the CCPMs disclosed in Tables 1, 2, or 5, herein, or the prognostic signatures disclosed in Tables 3, 4, 8A, 8B, and 9, but could involve the use of one or more CCPMs from the disclosed signatures, or a new signature may be established using CCPMs selected from the disclosed marker lists. 20 The requirement of any signature is that it predicts the likelihood of recurrence with enough accuracy to assist a medical practitioner to establish a treatment regime. Reverse Transcription PCR (RT-PCR) Of the techniques listed above, the most sensitive and most flexible 25 quantitative method is RT-PCR, which can be used to compare RNA levels in different sample populations, in normal and tumour tissues, with or without drug treatment, to characterize patterns of expression, to discriminate between closely related RNAs, and to analyze RNA structure. 30 For RT-PCR, the first step is the isolation of RNA from a target sample. The starting material is typically total RNA isolated from human tumours or tumour cell lines, and corresponding normal tissues or cell lines, respectively. RNA can be isolated from a variety of samples, such as tumour samples from breast, lung, colon (e.g., large bowel or small bowel), colorectal, gastric, esophageal, anal, rectal, 39 WO 2007/073220 PCT/NZ2006/000343 prostate, brain, liver, kidney, pancreas, spleen, thymus, testis, ovary, uterus, etc., tissues, from primary tumours, or tumour cell lines, and from pooled samples from healthy donors. If the source of RNA is a tumour, RNA can be extracted, for example, from frozen or archived paraffin-embedded and fixed (e.g., formalin-fixed) 5 tissue samples. The first step in gene expression profiling by RT-PCR is the reverse transcription of the RNA template into cDNA, followed by its exponential amplification in a PCR reaction. The two most commonly used reverse transcriptases 10 are avian myeloblastosis virus reverse transcriptase (AMV-RT) and Moloney murine leukaemia virus reverse transcriptase (MMLV-RT). The reverse transcription step is typically primed using specific primers, random hexamers, or oligo-dT primers, depending on the circumstances and the goal of expression profiling. For example, extracted RNA can be reverse-transcribed using a GeneAmp RNA PCR kit (Perkin 15 Elmer, CA, USA), following the manufacturer's instructions. The derived cDNA can then be used as a template in the subsequent PCR reaction. Although the PCR step can use a variety of thermostable DNA-dependent DNA polymerases, it typically employs the Taq DNA polymerase, which has a 5'-3' 20 nuclease activity but lacks a 3'-5' proofreading endonuclease activity. Thus, TaqMan (q) PCR typically utilizes the 5' nuclease activity of Taq or Tth polymerase to hydrolyze a hybridization probe bound to its target amplicon, but any enzyme with equivalent 5' nuclease activity can be used. 25 Two oligonucleotide primers are used to generate an amplicon typical of a PCR reaction. A third oligonucleotide, or probe, is designed to detect nucleotide sequence located between the two PCR primers. The probe is non-extendible by Taq DNA polymerase enzyme, and is labeled with a reporter fluorescent dye and a quencher fluorescent dye. Any laser-induced emission from the reporter dye is 30 quenched by the quenching dye when the two dyes are located close together as they are on the probe. During the amplification reaction, the Taq DNA polymerase enzyme cleaves the probe in a template-dependent manner. The resultant probe fragments disassociate in solution, and signal from the released reporter dye is free from the quenching effect of the second fluorophore. One molecule of reporter dye is 40 WO 2007/073220 PCT/NZ2006/000343 liberated for each new molecule synthesized, and detection of the unquenched reporter dye provides the basis for quantitative interpretation of the data. TaqMan RT-PCR can be performed using commercially available equipment, 5 such as, for example, ABI PRISM 7700 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA, USA), or Lightcycler (Roche Molecular Biochemicals, Mannheim, Germany). In a preferred embodiment, the 5' nuclease procedure is run on a real-time quantitative PCR device such as the ABI PRISM 7700tam Sequence Detection System. The system consists of a thermocycler, laser, 10 charge-coupled device (CCD), camera, and computer. The system amplifies samples in a 96-well format on a thermocycler. During amplification, laser-induced fluorescent signal is collected in real-time through fibre optics cables for all 96 wells, and detected at the CCD. The system includes software for running the instrument and for analyzing the data. 15 5' nuclease assay data are initially expressed as Ct, or the threshold cycle. As discussed above, fluorescence values are recorded during every cycle and represent the amount of product amplified to that point in the amplification reaction. The point when the fluorescent signal is first recorded as statistically significant is the threshold 20 cycle. To minimize errors and the effect of sample-to-sample variation, RT-PCR is usually performed using an internal standard. The ideal internal standard is expressed at a constant level among different tissues, and is unaffected by the experimental 25 treatment. RNAs most frequently used to normalize patterns of gene expression are mRNAs for the housekeeping genes glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and-actin. Real-time quantitative PCR (qPCR) 30 A more recent variation of the RT-PCR technique is the real time quantitative PCR, which measures PCR product accumulation through a dual-labeled fluorigenic probe (i.e., TaqMan probe). Real time PCR is compatible both with quantitative competitive PCR and with quantitative comparative PCR. The former uses an internal competitor for each target sequence for normalization, while the latter uses a 41 WO 2007/073220 PCT/NZ2006/000343 normalization gene contained within the sample, or a housekeeping gene for RT-PCR. Further details are provided, e.g., by Held et al., Genome Research 6: 986-994 (1996). Expression levels can be determined using fixed, paraffin-embedded tissues as 5 the RNA source. According to one aspect of the present invention, PCR primers and probes are designed based upon intron sequences present in the gene to be amplified. In this embodiment, the first step in the primer/probe design is the delineation of intron sequences within the genes. This can be done by publicly available software, such as the DNA BLAT software developed by Kent, W. J., Genome Res. 12 (4): 10 656-64 (2002), or by the BLAST software including its variations. Subsequent steps follow well established methods of PCR primer and probe design. In order to avoid non-specific signals, it is useful to mask repetitive sequences within the introns when designing the primers and probes. This can be easily 15 accomplished by using the Repeat Masker program available on-line through the Baylor College of Medicine, which screens DNA sequences against a library of repetitive elements and returns a query sequence in which the repetitive elements are masked. The masked sequences can then be used to design primer and probe sequences using any commercially or otherwise publicly available primer/probe 20 design packages, such as Primer Express (Applied Biosystems); MGB assay-by design (Applied Biosystems); Primer3 (Steve Rozen and Helen J. Skaletsky (2000) Primer3 on the WWW for general users and for biologist programmers in: Krawetz S, Misener S (eds) Bioinformatics Methods and Protocols: Methods in Molecular Biology. Humana Press, Totowa, NJ, pp 365-3 86). 25 The most important factors considered in PCR primer design include primer length, melting temperature (Tm), and G/C content, specificity, complementary primer sequences, and 3' end sequence. In general, optimal PCR primers are generally 17-30 bases in length, and contain about 20-80%, such as, for example, about 50-60% G+C 30 bases. Melting temperatures between 50 and 80'C, e.g., about 50 to 70*C, are typically preferred. For further guidelines for PCR primer and probe design see, e.g., Dieffenbach, C. W. et al., General Concepts for PCR Primer Design in: PCR Primer, A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 1995, pp. 133-155; Innis and Gelfand, Optimization of PCRs in: PCR Protocols, A Guide to 42 WO 2007/073220 PCT/NZ2006/000343 Methods and Applications, CRC Press, London, 1994, pp. 5-11; and Plasterer, T. N. Primerselect: Primer and probe design. Methods Mol. Biol. 70: 520-527 (1997), the entire disclosures of which are hereby expressly incorporated by reference. 5 Microarray analysis Differential expression can also be identified, or confirmed using the microarray technique. Thus, the expression profile of CCPMs can be measured in either fresh or paraffin-embedded tumour tissue, using microarray technology. In this method, polynucleotide sequences of interest (including cDNAs and oligonucleotides) 10 are plated, or arrayed, on a microchip substrate. The arrayed sequences (i.e., capture probes) are then hybridized with specific polynucleotides from cells or tissues of interest (i.e., targets). Just as in the RT-PCR method, the source of RNA typically is total RNA isolated from human tumours or tumour cell lines, and corresponding normal tissues or cell lines. Thus RNA can be isolated from a variety of primary 15 tumours or tumour cell lines. If the source of RNA is a primary tumour, RNA can be extracted, for example, from frozen or archived formalin fixed paraffin-embedded (FFPE) tissue samples and fixed (e.g., formalin-fixed) tissue samples, which are routinely prepared and preserved in everyday clinical practice. 20 In a specific embodiment of the microarray technique, PCR amplified inserts of cDNA clones are applied to a substrate. The substrate can include up to 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 75 nucleotide sequences. In other aspects, the substrate can include at least 10,000 nucleotide sequences. The microarrayed sequences, immobilized on the microchip, are suitable for hybridization under 25 stringent conditions. As other embodiments, the targets for the microarrays can be at least 50, 100, 200, 400, 500, 1000, or 2000 bases in length; or 50-100, 100-200, 100 500, 100-1000, 100-2000, or 500-5000 bases in length. As further embodiments, the capture probes for the microarrays can be at least 10, 15, 20, 25, 50, 75, 80, or 100 bases in length; or 10-15, 10-20, 10-25, 10-50, 10-75, 10-80, or 20-80 bases in length. 30 Fluorescently labeled cDNA probes may be generated through incorporation of fluorescent nucleotides by reverse transcription of RNA extracted from tissues of interest. Labeled cDNA probes applied to the chip hybridize with specificity to each spot of DNA on the array. After stringent washing to remove non-specifically bound 43 WO 2007/073220 PCT/NZ2006/000343 probes, the chip is scanned by confocal laser microscopy or by another detection method, such as a CCD camera. Quantitation of hybridization of each arrayed element allows for assessment of corresponding mRNA abundance. With dual colour fluorescence, separately labeled cDNA probes generated from two sources of RNA 5 are hybridized pairwise to the array. The relative abundance of the transcripts from the two sources corresponding to each specified gene is thus determined simultaneously. An exemplary protocol for this is described in detail in Example 4. The miniaturized scale of the hybridization affords a convenient and rapid 10 evaluation of the expression pattern for large numbers of genes. Such methods have been shown to have the sensitivity required to detect rare transcripts, which are expressed at a few copies per cell, and to reproducibly detect at least approximately two-fold differences in the expression levels (Schena et al., Proc. Natl. Acad. Sci. USA 93 (2): 106-149 (1996)). Microarray analysis can be performed by 15 commercially available equipment, following manufacturer's protocols, such as by using the Affymetrix GenChip technology, Illumina microarray technology or Incyte's microarray technology. The development of microarray methods for large-scale analysis of gene expression makes it possible to search systematically for molecular markers of cancer classification and outcome prediction in a variety of tumour types. 20 RNA isolation, purification, and amplification General methods for mRNA extraction are well known in the art and are disclosed in standard textbooks of molecular biology, including Ausubel et al., Current Protocols of Molecular Biology, John Wiley and Sons (1997). Methods for 25 RNA extraction from paraffin embedded tissues are disclosed, for example, in Rupp and Locker, Lab Invest. 56: A67 (1987), and De Sandres et al., BioTechniques 18: 42044 (1995). In particular, RNA isolation can be performed using purification kit, buffer set, and protease from commercial manufacturers, such as Qiagen, according to the manufacturer's instructions. For example, total RNA from cells in culture can be 30 isolated using Qiagen RNeasy mini-columns. Other commercially available RNA isolation kits include MasterPure Complete DNA and RNA Purification Kit (EPICENTRE (D, Madison, WI), and Paraffin Block RNA Isolation Kit (Ambion, Inc.). Total RNA from tissue samples can be isolated using RNA Stat-60 (Tel-Test). 44 WO 2007/073220 PCT/NZ2006/000343 RNA prepared from tumour can be isolated, for example, by cesium chloride density gradient centrifugation. The steps of a representative protocol for profiling gene expression using 5 fixed, paraffin-embedded tissues as the RNA source, including mRNA isolation, purification, primer extension and amplification are given in various published journal articles (for example: T. E. Godfrey et al. J. Molec. Diagnostics 2: 84-91 (2000); K. Specht et al., Am. J. Pathol. 158: 419-29 (2001)). Briefly, a representative process starts with cutting about 10 pm thick sections of paraffin-embedded tumour tissue 10 samples. The RNA is then extracted, and protein and DNA are removed. After analysis of the RNA concentration, RNA repair and/or amplification steps may be included, if necessary, and RNA is reverse transcribed using gene specific promoters followed by RT-PCR. Finally, the data are analyzed to identify the best treatment option(s) available to the patient on the basis of the characteristic gene expression 15 pattern identified in the tumour sample examined. Immunohistochemistry and proteomics Immunohistochemistry methods are also suitable for detecting the expression levels of the proliferation markers of the present invention. Thus, antibodies or 20 antisera, preferably polyclonal antisera, and most preferably monoclonal antibodies specific for each marker, are used to detect expression. The antibodies can be detected by direct labeling of the antibodies themselves, for example, with radioactive labels, fluorescent labels, hapten labels such as, biotin, or an enzyme such as horse radish peroxidase or alkaline phosphatase. Alternatively, unlabeled primary antibody 25 is used in conjunction with a labeled secondary antibody, comprising antisera, polyclonal antisera or a monoclonal antibody specific for the primary antibody. Immunohistochemistry protocols and kits are well known in the art and are commercially available. 30 Proteomics can be used to analyze the polypeptides present in a sample (e.g., tissue, organism, or cell culture) at a certain point of time. In particular, proteomic techniques can be used to assess the global changes of polypeptide expression in a sample (also referred to as expression proteomics). Proteomic analysis typically includes: (1) separation of individual polypeptides in a sample by 2-D gel 45 WO 2007/073220 PCT/NZ2006/000343 electrophoresis (2-D PAGE); (2) identification of the individual polypeptides recovered from the gel, e.g., by mass spectrometry or N-terminal sequencing, and (3) analysis of the data using bioinformatics. Proteomics methods are valuable supplements to other methods of gene expression profiling, and can be used, alone or 5 in combination with other methods, to detect the products of the proliferation markers of the present invention. Once the expression level of one or more prognostic markers in a tumour sample has been assessed the likelihood of the cancer recurring can then be determined. The 10 inventors have identified a number of markers that are differentially expressed in non recurring colorectal cancers compared to recurring colorectal cancers in patient data sets. The markers are set out in Tables 1, 2, and 9, in the examples below. Selection of Differentially Expressed Genes. 15 An early approach to the selection of genes deemed significant involved simply looking at the "fold change" of a given gene between the two groups of interest. While this approach hones in on genes that seem to change the most spectacularly, consideration of basic statistics leads one to realize that if the variance (or noise level) is quite high (as is often seen in microarray experiments), then seemingly large fold 20 change can happen frequently by chance alone. Microarray experiments, such as those described here, typically involve the simultaneous measurement of thousands of genes. If one is comparing the expression levels for a particular gene between two groups (for example recurrent and non 25 recurrent tumours), the typical tests for significance (such as the t-test) are not adequate. This is because, in an ensemble of thousands of experiments (in this context each gene constitutes an "experiment"), the probability of at least one experiment passing the usual criteria for significance by chance alone is essentially unity. In a test for significance, one typically calculates the probability that the "null 30 hypothesis" is correct. In the case of comparing two groups, the null hypothesis is that there is no difference between the two groups. If a statistical test produces a probability for the null hypothesis below some threshold (usually 0.05 or 0.01), it is stated that we can reject the null hypothesis, and accept the hypothesis that the two groups are significantly different. Clearly, in such a test, a rejection of the null 46 WO 2007/073220 PCT/NZ2006/000343 hypothesis by chance alone could be expected 1 in 20 times (or 1 in 100). The use of t-tests, or other similar statistical tests for significance, fail in the context of microarrays, producing far too many false positives (or type I errors) 5 In this type of situation, where one is testing multiple hypotheses at the same time, one applies typical multiple comparison procedures, such as the Bonferroni Method (43). However such tests are too conservative for most microarray experiments, resulting in too many false negative (type II) errors. 10 A more recent approach is to do away with attempting to apply a probability for a given test being significant, and establish a means for selecting a subset of experiments, such that the expected proportion of Type I errors (or false discovery rate; 47) is controlled for. It is this approach that has been used in this investigation, through various implementations, namely the methods provided with BRB Array 15 Tools (48), and the limma (11,42) package of Bioconductor (that uses the R statistical environment; 10,39). General methodology for Data Mining: Generation of Prognostic Signatures 20 Data Mining is the term used to describe the extraction of "knowledge", in other words the "know-how", or predictive ability from (usually) large volumes of data (the dataset). This is the approach used in this study to generate prognostic signatures. In the case of this study the "know-how" is the ability to accurately predict prognosis 25 from a given set of gene expression measurements, or "signature" (as described generally in this section and in more detail in the examples section). The specific details used for the methods used in this study are described in Examples 17-20. However, application of any of the data mining methods (both those described 30 in the Examples, and those described here) can follow this general protocol. Data mining (49), and the related topic machine learning (40) is a complex, repetitive mathematical task that involves the use of one or more appropriate computer software packages (see below). The use of software is advantageous on the one hand, in that 47 WO 2007/073220 PCT/NZ2006/000343 one does not need to be completely familiar with the intricacies of the theory behind each technique in order to successfully use data mining techniques, provided that one adheres to the correct methodology. The disadvantage is that the application of data mining can often be viewed as a "black box": one inserts the data and receives the 5 answer. How this is achieved is often masked from the end-user (this is the case for many of the techniques described, and can often influence the statistical method chosen for data mining. For example, neural networks and support vector machines have a particularly complex implementation that makes it very difficult for the end user to extract out the "rules" used to produce the decision. On the other hand, k 10 nearest neighbours and linear discriminant analysis have a very transparent process for decision making that is not hidden from the user. There are two types of approach used in data mining: supervised and unsupervised approaches. In the supervised approach, the information that is being linked to the 15 data is known, such as categorical data (e.g. recurrent vs. non recurrent tumours). What is required is the ability to link the observed response (e.g. recurrence vs. non recurrence) to the input variables. In the unsupervised approach, the classes within the dataset are not known in advance, and data mining methodology is employed to attempt to find the classes or structure within the dataset. 20 In the present example the supervised approach was used and is discussed in detail here, although it will be appreciated that any of the other techniques could be used. The overall protocol involves the following steps: 25 * Data representation. This involves transformation of the data into a form that is most likely to work successfully with the chosen data mining technique. In where the data is numerical, such as in this study where the data being investigated represents relative levels of gene expression, this is fairly simple. 30 If the data covers a large dynamic range (i.e. many orders of magnitude) often the log of the data is taken. If the data covers many measurements of separate samples on separate days by separate investigators, particular care has to be taken to ensure systematic error is minimised. The minimisation of systematic error (i.e. errors resulting from protocol differences, machine differences, 48 WO 2007/073220 PCT/NZ2006/000343 operator differences and other quantifiable factors) is the process referred to here as "normalisation". * Feature Selection. Typically the dataset contains many more data elements 5 than would be practical to measure on a day-to-day basis, and additionally many elements that do not provide the information needed to produce a prediction model. The actual ability of a prediction model to describe a dataset is derived from some subset of the full dimensionality of the dataset. These dimensions the most important components (or features) of the dataset. 10 Note in the context of microarray data, the dimensions of the dataset are the individual genes. Feature selection, in the context described here, involves finding those genes which are most "differentially expressed". In a more general sense, it involves those groups which pass some statistical test for significance, i.e. is the level of a particular variable consistently higher or 15 lower in one or other of the groups being investigated. Sometimes the features are those variables (or dimensions) which exhibit the greatest variance. The application of feature selection is completely independent of the method used to create a prediction model, and involves a great deal of experimentation to achieve the desired results. Within this invention, the selection of 20 significant genes, and those which correlated with the earlier successful model (the NZ classifier), entailed feature selection. In addition, methods of data reduction (such as principal component analysis) can be applied to the dataset. e Training. Once the classes (e.g. recurrence/non-recurrence) and the features of 25 the dataset have been established, and the data is represented in a form that is acceptable as input for data mining, the reduced dataset (as described by the features) is applied to the prediction model of choice. The input for this model is usually in the form a multi-dimensional numerical input,(known as a vector), with associated output information (a class label or a response). In the 30 training process, selected data is input into the prediction model, either sequentially (in techniques such as neural networks) or as a whole (in techniques that apply some form of regression, such as linear models, linear discriminant analysis, support vector machines). In some instances (e.g. k nearest neighbours) the dataset (or subset of the dataset obtained after feature 49 WO 2007/073220 PCT/NZ2006/000343 selection) is itself the model. As discussed, effective models can be established with minimal understanding of the detailed mathematics, through the use of various software packages where the parameters of the model have been pre-determined by expert analysts as most likely to lead to successful 5 results. * Validation. This is a key component of the data-mining protocol, and the incorrect application of this frequently leads to errors. Portions of the dataset are to be set aside, apart from feature selection and training, to test the success 10 of the prediction model. Furthermore, if the results of validation are used to effect feature selection and training of the model, then one obtains a further validation set to test the model before it is applied to real-life situations. If this process is not strictly adhered to the model is likely to fail in real-world situations. The methods of validation are described in more detail below. 15 * Application. Once the model has been constructed, and validated, it must be packaged in some way as it is accessible to end users. This often involves implementation of some form a spreadsheet application, into which the model has been imbedded, scripting of a statistical software package, or refactoring 20 of the model into a hard-coded application by information technology staff. Examples of software packages that are frequently used are: - Spreadsheet plugins, obtained from multiple vendors. - The R statistical environment. 25 - The commercial packages MatLab, S-plus, SAS, SPSS, STATA. - Free open-source software such as Octave (a MatLab clone) - many and varied C++ libraries, which can be used to implement prediction models in a commercial, closed-source setting. 30 Examples of Data Mining Methods. The methods can be by first performing the step of data mining process (above), and then applying the appropriate known software packages. Further description of the process of data mining is described in detail in many extremely well-written texts.(49) 50 WO 2007/073220 PCT/NZ2006/000343 " Linear models (49, 50): The data is treated as the input of a linear regression model, of which the class labels or responses variables are the output. Class labels, or other categorical data, must be transformed into numerical values 5 (usually integer). In generalised linear models, the class labels or response variables are not themselves linearly related to the input data, but are transformed through the use of a "link function". Logistic regression is the most common form of generalized linear model. 10 9 Linear Discriminant analysis (49, 51, 52). Provided the data is linearly separable (i.e. the groups or classes of data can be separated by a hyperplane, which is an n-dimensional extension of a threshold), this technique can be applied. A combination of variables is used to separate the classes, such that the between group variance is maximised, and the within-group variance is 15 minimised. The byproduct of this is the formation of a classification rule. Application of this rule to samples of unknown class allows predictions or classification of class membership to be made for that sample. There are variations of linear discriminant analysis such as nearest shrunken centroids which are commonly used for microarray analysis. 20 * Support vector machines (53): A collection of variables is used in conjunction with a collection of weights to determine a model that maximizes the separation between classes in terms of those weighted variables. Application of this model to a sample then produces a classification or prediction of class 25 membership for that sample. * Neural networks (52): The data is treated as input into a network of nodes, which superficially resemble biological neurons, which apply the input from all the nodes to which they are connected, and transform the input into an 30 output. Commonly, neural networks use the "multiply and sum" algorithm, to transform the inputs from multiple connected input nodes into a single output. A node may not necessarily produce an output unless the inputs to that node exceed a certain threshold. Each node has as its input the output from several other nodes, with the final output node usually being linked to a categorical 51 WO 2007/073220 PCT/NZ2006/000343 variable. The number of nodes, and the topology of the nodes can be varied in almost infinite ways, providing for the ability to classify extremely noisy data that may not be possible to categorize in other ways. The most common implementation of neural networks is the multi-layer perceptron. 5 " Classification and regression trees (54): In these. variables are used to define a hierarchy of rules that can be followed in a stepwise manner to determine the class of a sample. The typical process creates a set of rules which lead to a specific class output, or a specific statement of the inability to discriminate. A 10 example classification tree is an implementation of an algorithm such as: if gene A> x and gene Y > x and gene Z = z then class A else if geneA = q 15 then class B " Nearest neighbour methods (51, 52). Predictions or classifications are made by comparing a sample (of unknown class) to those around it (or known class), with closeness defined by a distance function. It is possible to define many 20 different distance functions. Commonly used distance functions are the Euclidean distance (an extension of the Pythagorean distance, as in triangulation, to n-dimensions), various forms of correlation (including Pearson Correlation co-efficient). There are also transformation functions that convert data points that would not normally be interconnected by a meaningful 25 distance metric into euclidean space, so that Euclidean distance can then be applied (e.g. Mahalanobis distance). Although the distance metric can be quite complex, the basic premise of k-nearest neighbours is quite simple, essentially being a restatement of "find the k-data vectors that are most similar to the unknown input, find out which class they correspond to, and 30 vote as to which class the unknown input is". " Other methods: - Bayesian networks. A directed acyclic graph is used to represent a collection of variables in conjunction with their joint probability distribution, which is 52 WO 2007/073220 PCT/NZ2006/000343 then used to determine the probability of class membership for a sample. - Independent components analysis, in which independent signals (e.g., class membership) re isolated (into components) from a collection of variables. These components can then be used to produce a classification or prediction of 5 class membership for a sample. Ensemble learning methods in which a collection of prediction methods are combined to produce a joint classification or prediction of class membership for a sample 10 There are many variations of these methodologies that can be explored (49), and many new methodologies are constantly being defined and developed. It will be appreciated that any one of these methodologies can be applied in order to obtain an acceptable result. Particular care must be taken to avoid overfitting, by ensuring that all results are tested via a comprehensive validation scheme. 15 Validation Application of any of the prediction methods described involves both training and cross-validation (43, 55) before the method can be applied to new datasets (such as 20 data from a clinical trial). Training involves taking a subset of the dataset of interest (in this case gene expression measurements from colorectal tumours), such that it is stratified across the classes that are being tested for (in this case recurrent and non recurrent tumours). This training set is used to generate a prediction model (defined above), which is tested on the remainder of the data (the testing set). 25 It is possible to alter the parameters of the prediction model so as to obtain better performance in the testing set, however, this can lead to the situation known as overfitting, where the prediction model works on the training dataset but not on any external dataset. In order to circumvent this, the process of validation is followed. 30 There are two major types of validation typically applied, the first (hold-out validation) involves partitioning the dataset into three groups: testing, training, and validation. The validation set has no input into the training process whatsoever, so that any adjustment of parameters or other refinements must take place during 53 WO 2007/073220 PCT/NZ2006/000343 application to the testing set (but not the validation set). The second major type is cross-validation, which can be applied in several different ways, described below. There are two main sub-types of cross-validation: K-fold cross-validation, and leave 5 one-out cross-validation K-fold cross-validation: .The dataset is divided into K subsamples, each subsample containing approximately the same proportions of the class groups as the original. In each round of validation, one of the K subsamples is set aside, and training is 10 accomplished using the remainder of the dataset. The effectiveness of the training for that round is guaged by how correctly the classification of the left-out group is. This procedure is repeated K- times, and the overall effectiveness ascertained by comparison of the predicted class with the known class. 15 Leave-one-out cross-validation: A commonly used variation of K-fold cross validation, in which K=n, where n is the number of samples. Combinations of CCPMS, such as those described above in Tables 1 and 2, can be used to construct predictive models for prognosis. 20 Prognostic Signatures Prognostic signatures, comprising one or more of these markers, can be used to determine the outcome of a patient, through application of one or more predictive models derived from the signature. In particular, a clinician or researcher can 25 determine the differential expression (e.g., increased or decreased expression) of the one or more markers in the signature, apply a predictive model, and thereby predict the negative prognosis, e.g., likelihood of disease relapse, of a patient, or alternatively the likelihood of a positive prognosis (continued remission). 30 A set of prognostic signatures have been developed. In the first instance, there are two signatures developed by cross-comparison of predictive ability between two datasets: the set of microarray experiments encompassing the German colorectal cancer samples, and the set of microarray experiments encompassing the New Zealand samples (discussed in example 6). In the second instance there has been an 54 WO 2007/073220 PCT/NZ2006/000343 exhaustive statistical search for effective signatures based solely on the German dataset (discussed in example 17). As described in Example 6 below, a prognostic signature comprising 19 genes has 5 been established from a set of colorectal samples from Germany (Table 4). Another prognostic signature, of 22 genes, has also been established from samples of colorectal tumours from patients in New Zealand (Table 3). By obtaining a patient sample (e.g., tumour sample), and matching the expression levels of one or more markers in the sample to the differential expression profile, the likelihood of the 10 cancer recurring can be determined. Table 3: New Zealand prognostic signature WDR44 WD repeat domain 44 0.81 Hs.98510 NM 019045 ma binding motif, single RBMS1 stranded interacting protein 1.27 Hs.470412 NM_016836 1, isoform d Ras-GTPase activating SACM1L protein SH3 domain-binding 0.84 Hs.156509 NM_014016 protein 2 sterol o-acyltransferase acyl SOATI coenzyme a: cholesterol 1.21 Hs.496383 NM_003101 acyltransferase 1 PBK pdz-binding kinase 0.76 Hs.104741 NM 018492 ras-gtpase activating protein G sh3 domain-binding protein 2 0.86 Hs.303676 NM_012297 ZBTB20 zinc finger and BTB domain 1.2 Hs.477166 NM_015642 ZBTB20_____ containing 20 ZNF4 10 zinc finger protein 410 0.84 Hs.270869 NM 021188 COMM domain containing COMMID2 2 1.09 Hs.591315 NM_016094 proteasome (prosome, PSMC1 macropain) 26s subunit, 0.79 Hs.356654 NM_002802 atpase, 1 COX10 homolog, COXlO cytochrome c oxidase assembly protein, heme A: 0.9 Hs.462278 NM_001303 farnesyltransferase (yeast) GTF3C5 general transcription factor 0.84 Hs.495417 NM_012087 ____________ific, polypeptide 5 (63kd) BAUMMR hyaluronan-mediated motility 0.78 Hs.72550 NM 012485 receptor (rhamm) M_ 012485 UBE2L3 ub tin-conjugating 0.83 Hs.108104 NM_003347 GNAS gnas complex locus 1.26 Hs.125898 NM 000516 protein phosphatase 2 PPP2R2A (formerly 2a), regulatory 0.91 Hs. 146339 NM_002717 subunit b (pr 52), alpha 55 WO 2007/073220 PCT/NZ2006/000343 isoform ribonuclease, rnase a family, RNASE2 2 (liver, eosinophil-derived 0.83 Hs.728 NM_002934 neurotoxin) SCOC short coiled-coil protein 0.78 Hs.480815 NM 032547 proteasome (prosome, PSMD9 macropain) 26s subunit, non- 0.89 Hs.131151 NM_002813 atpase, 9 eukaryotic translation ElF3S7 initiation factor 3, subunit 7 0.85 Hs.55682 NM_003753 (zeta, 66/67kd) ATP2B4 ATPase, Ca-H- transporting, 1.11 Hs.343522 NM_001001396 plasma membrane 4 NM 001684 atp-binding cassette, sub ABCC9 family c, member 9, isoform 0.9 Hs.446050 NM_020298 sur2a-delta-14 Table 4: German prognostic signature Expression Gene Symbol Gene Description fold difference UniGene GenBank (relapse/non- Cluster Acc. No. relapse) Chemokine (C-X-C motif) CXCL10 ligand 10 0.87 Hs.413924 NM 001565 NM_000043 NM_152871 NM 152872 NM_152873 NM_152874 NM_152875 FAS (TNF receptor NM_152876 FAS superfamily, member 6) 0.9 Hs.244139 NM 152877 chemokine (C-X-C motif) CXCL9 ligand 9 0.87 Hs.77367 NM 002416 TLK1 tousled-like kinase 1 0.91 Hs.470586 NM 012290 chemokine (C-X-C motif) CXCL11 ligand 11 0.75 Hs.518814 NM 005409 T-LAK cell-originated PBK protein kinase 0.86 Hs.104741 NM 018492 phosphoserine PSATI aminotransferase 1 0.91 Hs.494261 NM 021154 MAD2 mitotic arrest MAD2L1 deficient-like 1 (yeast) 0.89 Hs.533185 NM 002358 CA2 carbonic anhydrase II 0.84 Hs.155097 NM 000067 granzyme B (granzyme 2, cytotoxic T-lymphocyte GZMB associated serine esterase 1) 0.9 Hs.1051 NM 004131 solute carrier family 4, sodium bicarbonate SLC4A4 cotransporter, member 4 0.86 Hs.5462 NM 003759 discs, large homolog 7 DLG7 (Drosophila) 0.89 Hs.77695 NM 014750 tumor necrosis factor TNFRSF11A receptor superfamily, 0.9 Hs.204044 NM 003839 56 WO 2007/073220 PCT/NZ2006/000343 Expression Gene Symbol Gene Description fold difference UniGene GenBank (relapse/non- Cluster Acc. No. relapse) member 11 a, activator of NFKB KITLG KIT ligand 0.91 Hs.1048 NM 000899 indoleamine-pyrrole 2,3 INDO dioxygenase 0.91 Hs.840 NM 002164 guanylate binding protein 1, GBP1 interferon-inducible, 67kDa 0.9 Hs.62661 NM 002053 chemokine (C-X-C motif) ligand 13 (B-cell CXCL13 chemoattractant) 0.86 Hs.100431 NM 006419 chloride channel, calcium CLCA4 activated, family member 4 0.84 Hs.546343 NM 012128 PCP4 Purkinje cell protein 4 1.14 Hs.80296 NM 006198 Table 5: Immune response genes Expression Gene Symbol Gene Description fold difference UniGene GenBank (relapse/non- Cluster Acc. No. relapse) chemokine (C-X-C motif) CXCL9 ligand 9 0.87 Hs.77367 NM 002416 Chemokine (C-X-C motif) CXCL1O ligand 10 0.87 Hs.413924 NM 001565 chemokine (C-X-C motif) CXCL11 ligand 11 0.75 Hs.518814 AF030514 chemokine (C-X-C motif) ligand 13 (B-cell CXCL13 chemoattractant) 0.86 Hs.100431 NM 006419 T-LAK cell-originated PBK protein kinase 0.86 Hs.104741 NM 018492 indoleamine-pyrrole 2,3 INDO dioxygenase 0.91 Hs.840 M34455 guanylate binding protein 1, GBP1 interferon-inducible, 67kDa 0.9 Hs.62661 NM 002053 granzyme B (granzyme 2, cytotoxic T-lymphocyte GZMB associated seine esterase 1) 0.9 Hs.1051 J03189 KITLG KIT ligand 0.91 Hs.1048 NM 000899 tumor necrosis factor receptor superfamily, member 11 a, activator of TNFRSF11A NFKB 0.9 Hs.204044 NM 003839 FAS (TNF receptor FAS superfamily, member 6) 0.9 Hs.244139 Z70519 In certain aspects, this invention provides methods for determining the prognosis of a 5 cancer, comprising: (a) providing a sample of the cancer; (b) detecting the expression 57 WO 2007/073220 PCT/NZ2006/000343 level of a CCPM family member in said sample; and (c) determining the prognosis of the cancer. In one aspect, the cancer is colorectal cancer. In other aspects, the invention includes a step of detecting the expression level of a 5 CCPM mRNA. In other aspects, the invention includes a step of detecting the expression level of a CCPM polypeptide. In yet a further aspect, the invention includes a step of detecting the level of a CCPM peptide. In yet another aspect, the invention includes detecting the expression level of more than one CCPM family member in said sample. In a further aspect the CCPM is a gene associated with an 10 immune response. In a further aspect the CCPM is selected from the markers set forth in Tables 3, 4, 8A, 8B, or 9. In a still further aspect, the CCPM is included in a signature selected from the signatures set forth in Tables 3, 4, 8A, 8B, or 9. In a further aspect the invention comprises detecting the expression level of; WDR44, 15 RBMS1, SACM1L, SOATI, PBK, G3BP2, ZBTB20, ZNF410, COMMD2, PSMC1, COX10, GTF3C5, HMMR, UBE2L3, GNAS, PPP2R2A, RNASE2, SCOC PSMD9, EIF3S7, ATP2B4, and ABCC9. In a further aspect the invention comprises detecting the expression level of; CXCL1O, FAS, CXCLO, TLK1, CXCL11, PBK, PSAT1, MAD2L1, CA2, GZMB, SLC4A4, DLG7, TNFRSF11A, KITLG, INDO, GBP1, 20 CXCL13, CLCA4, and PCP4. In still further aspects, the invention includes a method of determining a treatment regime for a cancer comprising: (a) providing a sample of the cancer; (b) detecting the expression level of a CCPM family member in said sample; (c) determining the 25 prognosis of the cancer based on the expression level of a CCPM family member; and (d) determining the treatment regime according to the prognosis. In still further aspects, the invention includes a device for detecting a CCPM, comprising: a substrate having a CCPM capture reagent thereon; and a detector 30 associated with said substrate, said detector capable of detecting a CCPM associated with said capture reagent. Additional aspects include kits for detecting cancer, comprising: a substrate; a CCPM capture reagent; and instructions for use. Yet further aspects of the invention include method for detecting a CCPM using qPCR, 58 WO 2007/073220 PCT/NZ2006/000343 comprising: a forward primer specific for said CCPM; a reverse primer specific for said CCPM; PCR reagents; a reaction vial; and instructions for use. Additional aspects of this invention comprise a kit for detecting the presence of a 5 CCPM polypeptide or peptide, comprising: a substrate having a capture agent for said CCPM polypeptide or peptide; an antibody specific for said CCPM polypeptide or peptide; a reagent capable of labeling bound antibody for said CCPM polypeptide or peptide; and instructions for use. 10 In yet further aspects, this invention includes a method for determining the prognosis of colorectal cancer, comprising the steps of: providing a tumour sample from a patient suspected of having colorectal cancer; measuring the presence of a CCPM polypeptide using an ELISA method. In specific aspects of this invention the CCPM of the invention is selected from the markers set forth in Tables 1, 2, 5, or 9. In still 15 further aspects, the CCPM is included in a prognostic signature selected from the signatures set forth in Tables 3, 4, 8A, 8B, or 10. EXAMPLES The examples described herein are for purposes of illustrating embodiments of the 20 invention. Other embodiments, methods, and types of analyses are within the scope of persons of ordinary skill in the molecular diagnostic arts and need not be described in detail hereon. Other embodiments within the scope of the art are considered to be part of this invention. 25 Example 1: Patients and methods Two cohorts of patients were included in this study, one set from New Zealand (NZ) and the second from Germany (DE). The NZ patients were part of a prospective cohort study that included all disease stages, whereas the DE samples were selected from a tumour bank. Clinical information is shown in Table 6, while Figure 1 30 summarises the experimental design. Example 2: Tumour samples Primary colorectal tumor samples from 149 NZ patients were obtained from patients undergoing surgery at Dunedin Hospital and Auckland Hospital between 1995-2000. 59 WO 2007/073220 PCT/NZ2006/000343 Tumor samples were snap frozen in liquid nitrogen. All surgical specimens were reviewed by a single pathologist (H-S Y) and were estimated to contain an average of 85% tumor cells. Among the 149 CRC patients, 12 had metastatic disease at presentation, 35 developed recurrent disease, and 102 were disease-free after a 5 minimum of 5-year follow up. Primary colorectal tumor samples from DE patients were obtained from patients undergoing surgery at the Surgical Department of the Technical University of Munich between 1995-2001. A group of 55 colorectal carcinoma samples was selected from 10 banked tumours which had been obtained fresh from surgery, snap frozen in liquid nitrogen. The samples were obtained from 11 patients with stage I cancer and 44 patients with stage II cancer. Twenty nine patients were recurrence-free and 26 patients had experienced disease recurrence after a minimum of 5-year follow up. Tumor content ranged between 70 and 100% with an average of 87%. 15 60 WO 2007/073220 PCT/NZ2006/000343 Table 6: Clinical characteristics of New Zealand and German colorectal tumours 1. Persisting disease New Zealand data Relapse free _ Relapse Number of patients 102 47 Age 68.5 (SD: 15.1) 69.8 (SD: 8.7) Gender male 48 (47%) 22 (47%) female 54 (53%) 25 (53%) Tumor localization right colon 41(40%) 18(38%) left colon 12(12%) 4(9%) sigmoid 31(30%) 17(36%) rectum 18(18%) 8(17%) Tumor stage Stage I 16 0 Stage 11 61 13 Stage Ill 25 22 Stage IV 0 121 Median follow up period/median recurrence free period 72 (range: 60-80) 15 (range: 0-59) (months) G"'erIman data Relapse free Relapse Number of patients 29 26 Age 64.3 (SD: 12.8) 61.8 (SD:10.7) Gender male 17 (59%) 16 (62%) female 12 (41%) 10 (38%) Tumor localization right colon 8 (28%) 4 (15%) left colon 7 (24%) 5 (19%) sigmoid 6 (21%) 7 (27%) rectum 8 (28%) 10 (38%) Tumor stage Stage 1 5 6 Stage II 24 20 Median follow up period/median 83.1 (range: 64-99) 27.4 (range: 3-60) recurrence free period (months) 5 Example 3: RNA Extraction and target labeling NZ tumours: Tumours were homogenized and RNA was extracted using Tri-Reagent (Progenz, Auckland, New Zealand). The RNA was then further purified using RNeasy mini column (Qiagen, Victoria, Australia). Ten micrograms of RNA was labelled with Cy5 dUTP using the indirect amino-allyl cDNA labelling protocol. A 10 reference RNA from 12 different cell lines was labelled with Cy3 dUTP. The 61 WO 2007/073220 PCT/NZ2006/000343 fluorescently labelled CDNA were purified using a QiaQuick PCR purification kit (Qiagen, Victoria, Australia) according to the manufacturer's protocol. DE tumours: Tumours were homogenized and RNA was isolated using RNeasy Mini 5 Kit (Qiagen, Hilden, Germany). cRNA preparation was performed as described previously (9), purified on RNeasy Columns (Qiagen, Hilden, Germany), and eluted in 55 L of water. Fifteen micrograms of cRNA was fragmented for 35 minutes at 95*C and double stranded cDNA was synthesized with a oligo-dT-T7 primer (Eurogentec, K61n, Germany) and transcribed using the Promega RiboMax T7-kit 10 (Promega, Madison, WI) and Biotin-NTP labelling mix (Loxo, Dossenheim, Germany). Example 4: Microarray experiments NZ tumours: Hybridisation of the labelled target cDNA was performed using MWG 15 Human 30K Array oligonucleotides printed on epoxy coated slides. Slides were blocked with 1% BSA and the hybridisation was done in pre-hybridisation buffer at 42"C for at least 12 hours followed by a high stringency wash. Slides were scanned with a GenePix Microarray Scanner and data was analyzed using GenePix Pro 4.1 Microarray Acquisition and Analysis Software (Axon, CA). 20 DE tumours: cRNA was mixed with B2-control oligonucleotide (Affymetrix, Santa Clara, CA), eukaryotic hybridization controls (Affymetrix, Santa Clara, CA), herring sperm (Promega, Madison, WI), buffer and BSA to a final volume of 300 pl and hybridized to one microarray chip (Affymetrix, Santa Clara, CA) for 16 hours at 25 45'C. Washing steps and incubation with streptavidin (Roche, Mannheim, Germany), biotinylated goat-anti streptavidin antibody (Serva, Heidelberg, Germany), goat-IgG (Sigma, Taufkirchen, Germany), and streptavidin-phycoerythrin (Molecular Probes, Leiden, Netherlands) was performed in an Affymetrix Fluidics Station according to the manufacturer's protocol. The arrays were then scanned with a HP-argon-ion laser 30 confocal microscope and the digitized image data were processed using the Affymetrix@ Microarray Suite 5.0 Software. 62 WO 2007/073220 PCT/NZ2006/000343 Example 5: Data pre-processing NZ data: Data pre-processing and normalization was performed in the R computing environment (10). A log2 transformation was applied to the foreground intensities from each channel of each array. Data from each spot was used on a per array basis to 5 perform print-tip loss normalization via the limma package (11) from the Bioconductor suite of analysis tools (12). Scale normalization (13) was then used to standardize the distribution of log intensity ratios across arrays. Post-normalization cluster analysis revealed the presence of a gene-specific print-run effect present in the data. Analysis of variance (ANOVA) normalization was used to estimate and remove 10 print run effects from the data for each gene. Replicate array data was available for 46 of the 149 samples. Cluster analysis of the entire data set indicated that the duplicate arrays clustered well with each other suggesting internal consistency of the array platform. Genes with low intensity, large differences between replicates (mean log2 difference between duplicates higher than 0.5), and unknown proteins were 15 removed from the data set. After the initial normalization procedure, a subset of 10,318 genes was chosen for further analysis. DE data: All Affymetrix U133A GeneChips passed quality control to eliminate scans with abnormal characteristics, that is, abnormal low or high dynamic range, high 20 perfect match saturation, high pixel noise, grid misalignment problems, and low mean signal to noise ratio. Background correction and normalization were performed in the R computing environment (10, 40). Background corrected and normalized expression measures from probe level data (cel-files) were obtained using the robust multi-array average function (14) implemented in the Bioconductor package affy. 25 Example 6: Prognostic signatures and cross validation Data analysis was performed using the BRB Array-Tools package (hypertext transfer protocol://linus.nci.nih.gov/BRB-ArrayTools.html). Gene selection was performed using a random variance model t-test. In the DE data, 318 genes were found to be 30 differentially expressed when using a significance threshold of 0.001. As most of the differentially expressed genes exhibited relatively small changes in expression, a condition requiring the mean log2 fold change between the two classes to be higher than 1.1 was added to the gene selection process for the DE data. Gene-based prognostic signatures were produced using leave one out cross validation (LOOCV) 63 WO 2007/073220 PCT/NZ2006/000343 in each of the NZ and DE data sets. To avoid the problem of over-fitting, both the gene selection and signature construction were performed during each LOOCV iteration. After LOOCV, the prediction rate was estimated by the fraction of samples correctly predicted. In order to find a gene set that could make the best prediction for 5 unknown samples, different t-test thresholds using a random variance model were investigated in conjunction with six classification methods: compound covariate classifier (CCP), diagonal linear discriminant analysis (DLD), 3- nearest neighbours (3-NN), 1- nearest neighbours (1-NN), nearest centroid (NC), and support vector machines (SVM). 10 To establish the validity of the NZ and DE prognosis signatures, reciprocal validation was performed, with the NZ signature validated using the DE data set, and vice versa. To test the NZ genes, probes relating to the 22 genes from the NZ signature were identified in the DE data, and LOOCV was used to assess the performance of a 15 signature for the DE samples, based only on these probes. Similarly, probes relating to the 19 genes in the DE signature were identified in the NZ data and LOOCV was used to assess the performance of a signature for the NZ samples. In both cases a significance threshold of 0.999 was used to ensure that all genes were used in each LOOCV iteration. Differences between the platforms (in particular, log-ratio data 20 versus log-intensity data) meant that direct application of a prediction rule across data sets was not feasible. The consequence of this is that only the gene sets, and not the prediction rules used, can be generalized to new samples. The significance of the LOOCV prediction results was calculated by permuting the class labels of the samples and finding the proportion of times that the permuted data resulted in a higher 25 LOOCV prediction rate than that obtained for the unpermuted data. All permutation analysis involved 2000 permutations, with small P-values indicating that prediction results were unlikely to be due to chance. Example 7: Survival analysis 30 Kaplan-Meier survival analysis for censored data was performed using the survival package within the R computing environment. Survival was defined to be "disease free survival" post surgery. For each analysis, survival curves were constructed, and the log-rank test (15) was used to assess the presence of significant differences between the curves for the two groups in question. Censoring was taken into account 64 WO 2007/073220 PCT/NZ2006/000343 for both the NZ and DE data sets. For the disease-free survival data, right censoring prior to five years could only occur for non-recurrent patients as a result of either death, or the last clinical follow-up occurring at less than five years. Odds ratios and confidence intervals were produced using the epitools package for R. 5 Example 8: Identification of markers co-expressed with chemokine ligands Genes in the DE data which had a Pearson correlation coefficient greater than 0.75 with at least one of the four chemokines appearing in the predictor in the non-relapse group were selected for ontology analysis. Ontology was performed using DAVID 10 (hypertext transfer protocol://apps1.niaid.nih.gov/david/). Example 9: Results and analysis To identify robust prognostic signatures to predict disease relapse for CRC, two independent sets of samples from NZ and DE were used to generate array expression 15 data sets from separate series of primary tumours with clinical follow-up of five or more years. After normalization, each data set was analyzed using the same statistical methods to generate a prognostic signature, which was then validated on the alternate series of patients. As such, the DE prognostic signature was validated on the NZ data set and the NZ prognostic signature was validated on the DE data set. 20 Example 10: Exhaustive Identification of differentially expressed markers DE Data Set: The BRB Array Tools class comparison procedure was used to detect probes exhibiting statistically significant differences in average intensity between relapse and non-relapse samples. The RVM (random variance model) was again used 25 to produce p-values for each probe in the data set. In this second round, a total of 325 probes were found to be significantly differentially expressed between the two sample classes using an arbitrary significance threshold of 0.05. Note this selection of genes did not apply any fold-change threshold, and used a significance cut off of 0.05, rather than the threshold of 0.001 that was used in Example 6. The purpose of this less 30 stringent threshold (p=0.05 instead of p=0.001) was to put forward a larger number of genes for construction of the second round of signatures (see example 17) These probes represent 270 unique genes (Table 1 and Table 2). 65 WO 2007/073220 PCT/NZ2006/000343 Explicitly, the test for significance (random variance model) comprises the following: generating a test statistic for each gene which was identical to that of a standard two sample t-test (45) except that the estimate of the pooled variance was obtained by representing the variance structure across all genes as an F-distribution, and then 5 using the parameters, a and b, of this distribution (obtained via maximization of the empirical likelihood function) to form the following estimate of the pooled variance (see next page), 2(n - 2)S ,2,, + 2b S 2=( 2) pooled (n - 2)+2a 10 where S2 is the new estimate of the pooled variance, S 2 poord is the standard estimate of pooled variance (45), n is the number of samples, and a and b are the parameters of the F-distribution (46). Based on the t-statistic formed, a t-distribution with n-2+2a degrees of freedom was used to obtain a p-value for each gene. To adjust for multiple 15 hypothesis testing, the False Discovery Rate controlling procedure of Benjamini and Hochberg (7) was used to produce adjusted p-values for each gene. A gene was considered to have undergone significant differential expression if its adjusted p-value was less than 0.05. 20 Example 11: Identification of correlated markers In order to identify additional genes that can be used as prognostic predictors, correlation analysis was carried out using the R statistical computing software package. This analysis revealed 167 probes that had a Pearson correlation coefficient (40, 44, 45) of at least 0.8. Of these probes, 51 were already present in the set of 325 25 significantly differentially expressed probes, while the remaining 116 were reported as non-significant (using a 0.05 threshold for the FDR, or "false-discovery rate" (47) controlling procedure, the RVM, or rando variance model). These 116 probes represent 111 distinct genes (Table 2). 30 Example 12: Construction of prognostic signatures The NZ data set was generated using oligonucleotide printed microarrays. Six different signatures were constructed, with a support vector machine (SVM) using a 66 WO 2007/073220 PCT/NZ2006/000343 gene selection threshold of 0.0008 yielding the highest LOOCV prediction rate, and producing a 2 2-gene signature (77% prediction rate, 53% sensitivity, 88% specificity; p=0.002, Tables 7, 8A, and 8B). For Tables 8A and 8B, the gene descriptions are shown in Tables 3 and 4, respectively. 5 Table 7: Construction of prognostic signatures 22 gene NZ signature tested on German data Data set Prediction rate Sensitivity Specificity P value* Odd ratio NZ data ( training; SVM) 0.77 (0.66, 0.86)§ 0.53 (0.33, 0.73) 0.88 (0.77, 0.95) 0.002 8.4 (3.5, 21.4) NZ data minus 4 genes not found in German data were removed from 0.72 0.38 0.87 0.011 NZ data set (training; SVM)' German data (test; SVM) 0.71 (0.51, 0.86) 0.62 (0.32, 0.86) 0.79 (0.52, 0.95) 0.002 5.9 (1.6,24.5) 19 gone Gernwn s~ntrtseon ta Data set Prediction rate Sensitivity Specificity P value * Odd ratio German data (training; 3-NN) 0.84 (0.65, 0.95) 0.85 0.83 <0.0001 24.1 (5.3, 144.7) German data minus 5 genes not found in NZ data were removed 0.67 0.65 0.66 0.046 from German data set (training; 3 NN) NZ data (test; 3-NN) 0.67 (0.55, 0.78) 0.42 (0.22, 0.64) 0.78 (0.65, 0.89) 0.045 2.6 (1.2, 6.0) SVM: support vector machine signature; 3-NN: 3 nearest neighbour signature. § 95% confidence interval * P values were calculated from 2,000 permutation of class labels Table 8A: NZ prognostic signature New Zealand 22-gene prognostic signature p-value Gene Symbol GenBank Acc. No. Genes not found in German data at time of analysis 2.30E-05 WDR44 NM 019045 * 3.30E-05 RBMS1 NM 016836 4.60E-05 SACMIL NM 014016 6.80E-05 SOATI NM 003101 7.90E-05 PBK NM 018492 0.00014 G3BP2 NM 012297 0.000163 ZBTB20 NM 015642 0.000214 ZNF410 NM 021188 * 0.00022 COMMD2 NM 016094 * 0.000293 PSMC1 NM 002802 0.000321 COX1O NM 001303 0.000334 GTF3C5 NM 012087 0.000367 HMMR NM 012485 0.000405 UBE2L3 NM 003347 0.000417 GNAS NM 000516 0.000467 PPP2R2A NM 002717 0.000493 RNASE2 NM 002934 0.000532 SCOC NM 032547 * 0.000578 PSMD9 NM 002813 67 WO 2007/073220 PCT/NZ2006/000343 0.000593 EIF3S7 NM 003753 0.000649 ATP2B4 NM_001001396 NM_001684 0.000737 ABCC9 NM 020298 Table 8B: DE prognostic signature German 19-gene prognostic signature p-value Gene Symbol GenBank Genes not found in NZ data Acc. No. at time of analysis 3.OOE-06 CXCL1O NM 001565 4.OOE-06 FAS NM_000043 NM_152871 NM_152872 NM_152873 NM_152874 NM_152875 NM_152876 NM 152877 8.OOE-06 CXCL9 NM 002416 * 1.20E-05 TLK1 NM 012290 1.30E-05 CXCL11 NM 005409 2.10E-05 PBK NM 018492 4.20E-05 PSATI NM 021154 7.60E-05 MAD2L1 NM 002358 9.80E-05 CA2 NM 000067 0.000128 GZMB NM 004131 * 0.000177 SLC4A4 NM 003759 0.000215 DLG7 NM 014750 * 0.000376 TNFRSF11A NM 003839 0.00038 KITLG NM 000899 0.000579 INDO NM 002164 0.000634 GBP1 NM 002053 0.000919 CXCL13 NM 006419 * 0.000942 CLCA4 NM 012128 * 0.001636 PCP4 NM 006198 5 The NZ signature had an odds ratio for disease recurrence in the NZ patients of 8.4 (95% CI 3.5-21.4). The DE data set was generated using Affymetrix arrays resulting in a 19-gene (22 10 probe) and 3-nearest neighbour (3-NN) signature (selection threshold 0.002, log2 fold change>1.1, 84% classification rate, 85% sensitivity, 83% specificity, p<0.0001, Tables 3, 4, 7). The DE signature had an odds ratio for recurrence in the DE patients of 24.1 (95% CI 5.3-144.7). Using Kaplan-Meier analysis, disease-free survival in NZ and DE patients was significantly different for those predicted to recur or not 15 recur (NZ signature, p<0.0001, Fig. 2A; DE signature, p<0.0001, Fig. 2B). 68 WO 2007/073220 PCT/NZ2006/000343 Example 13: External validation of the NZ and DE prognostic signatures To validate the NZ signature, the 22 genes were used to construct a SVM signature in the DE data set by LOOCV. A prediction rate of 71% was achieved, which was 5 highly significant (p=0.00 2 ; Table 7). The odds ratio for recurrence in DE patients, using the NZ signature, was 5.9 (95% CI 1.6-24.5). We surmise that the reduction in prediction rate, from 77% in NZ patients to 71% in DE patients (Table 7), was due to four genes from the NZ signature not being present in the DE data. Disease-free survival for DE patients predicted to relapse, according to the NZ signature, was 10 significantly lower than disease-free survival for patients predicted not to relapse (p=0.0049, Fig. 2C). The DE signature was next validated by using the 19 genes to construct a 3-NN signature in the NZ data set by LOOCV. The prediction rate of 67% was again 15 significant (p=0.046; Table 7), confirming the validity of the DE signature. The odds ratio for recurrence in NZ patients, using the DE signature, was 2.6 (95% CI 1.2-6.0). We consider that the reduction of the prediction rate was due to five genes from DE signature not being present in the NZ data set. This was confirmed when removal of these five genes from the DE data set resulted in a reduction of the LOOCV prediction 20 rate from 84% to 67% (Table 7). Disease-free survival for NZ patients predicted to relapse, according to the DE signature, was significantly lower than disease-free survival for patients predicted not to relapse (p=0.029; Fig. 2D). Example 14: Comparison of NZ and DE prognostic signatures with current staging 25 system Significant differences in disease-free survival between patients predicted to relapse or not relapse were also observed within the same clinico-pathological stage (Figure 3). When patient predictions were stratified according to disease stage, the NZ signature was able to identify patients who were more likely to recur in both Stage II 30 (p=0.0013, Fig. 3A), and Stage III subgroups (p=0.0295, Fig. 3A). This was mirrored to a lesser extent when the DE signature was applied to the NZ data set, where the difference was only observed for Stage III patients (p=0.0491, Fig. 3B). Again, the decreased predictive accuracy of the DE signature was likely due to the absence of five genes from the NZ data that decreased the LOOCV prediction rate. 35 69 WO 2007/073220 PCT/NZ2006/000343 Example 15: Genes in signatures are related to CRC disease progression A number of genes in the NZ signature (Table 3) including G3BP2 (16), RBMS1 (17), HMMR (18), UBE2L3 (19), GNAS (20), RNASE2 (21) and ABCC9 (22) have all been reported to be involved in cancer progression, while RBMS1 (23), EIF3S7 5 (24) and GTF3C5 (25) are involved in transcription or translation. PBK is a protein kinase, which is involved in the process of mitosis (26), and the only gene common to the NZ and DE signatures. Eleven of 19 genes in the DE signature (Table 4) are involved in the immune response including 4 chemokine ligands (CXCL9, CXCL10, CXCL11, CXCL13;'(27)), PBK (28), INDO (29), GBP1 (30), GZMB (31), KITLG 10 (32), and two receptors of the tumor necrosis factor family (TNFRSF1 1A, FAS; 33)). Eighty six genes were found to be moderately correlated (Pearson correlation coefficient > 0.75) with at least one of the four chemokine ligands in the DE data. Ontology analysis found that 39 of these 65 genes were in the category of immune 15 response (p<10-26). This result suggests a key role for the host immune response in determining CRC recurrence. Example 16: Discussion of NZ and DE Prognostic Signatures It has been shown that the two different prognostic signatures can be used to improve 20 the current prognosis of colorectal cancer. For the DE signature, it was surprising and unexpected that the stage 1/11 samples could be used to predict stage III outcome. It was also surprising that many genes associated with recurrent disease are related to the immune response. The immune 25 response has an important role in the progression of different cancers and T lymphocyte infiltration in CRC patients is an indicator of good prognosis (36-38). All of the eleven immune response (Table 5) genes were down-regulated in recurrent patients which would be unexpected based on known biological mechanisms. 30 To further confirm these results, 4 chemokine genes were chosen for further analysis. Chemokine ligands not only reflect the activity of the immune system and mediate leukocyte recruitment but also are involved in chemotaxis, cell adhesion and motility, and angiogenesis (36). To investigate the role of the immune response genes, 86 genes co-expressed with the chemokine ligands were identified. Almost half of these 35 genes had a Gene Ontology classification within the "immune response" category 70 WO 2007/073220 PCT/NZ2006/000343 suggesting that the primary function of these genes in the recurrence process is the modulation of the immune response. Furthermore, CD4+ and CD8+ T cell antigens (CD8A, CD3, PRF1, TRA@, TRB@) or functionally related antigens, for example, major histocompatibility molecules, interferon gamma induced proteins, and IL2RB, 5 were found in the co-expressed gene list. The activation of tumor specific CD4+ T cells and CD8+ T cells has been shown to result in tumour rejection in a mouse colorectal cancer model (37). Collectively, these findings suggest that the lyphocytes form part of a tumor-specific host response involved in minimising the spread of cells from the primary tumour. 10 Example 17: Selection of additional prognostic signatures The performance of the two prognostic signatures described above was excellent in terms of cross-validation between the two data sets. Further studies were carried out, using a purely statistical approach, to develop a range of signatures, in addition to the 15 aforementioned, that would also predict prognosis for other data sets. One of the additional goals of these studies was to ensure that the method used to normalize the microarray data (robust multi-array average) was not exerting undue influence on the choice of genes. 20 Figure 4 shows the classification rates obtained from signatures of varying lengths. The classification rate is the proportion of correct relapse predictions (expressed as a percentage of total predictions), i.e., the proportion of samples correctly classified. The classification rates were determined using 11-fold cross validation. For this cross validation, a randomly selected stratified sample (i.e. same ratio of recurrent to non 25 recurrent tumours as the full data set) was removed as a validation set prior to gene selection of the genes, and model construction (using the training set of the remaining 50 samples). Cross-validation was then repeated a further ten times so that all 55 samples appeared in one validation set each. This 11-fold cross-validation process was repeated as 10 replicates, and the results plotted in Figure 4 and Figure. The 30 classification rates shown were corrected using bootstrap bias correction (43), to give the expected classification rates for the signatures to be applied to another data set. From this analysis, it was ascertained that shorter signatures produced the best classification rate. In addition, analysis of the genes that most frequently appeared in classifiers show that the discriminatory power was mostly due to the effectiveness of 71 WO 2007/073220 PCT/NZ2006/000343 two genes: FAS and ME2. This is illustrated most clearly by figure 5 shows the effectiveness of the signatures, once the two genes FAS and ME2 were removed from the data set. For more detail see the legend to Figure 5. 5 The effect of normalization on feature selection was thoroughly investigated by generating gene lists from 1000 stratified sub-samples of the original set of tumours, each time removing 5 samples (i.e. 1/11 of the total number of samples) from the data set. (This is effectively the same as performing 11-fold cross-validation). A tally was made of the number of times each gene appeared in the "top-n" gene lists (i.e., top 10, 10 top 20, top 100, and top 325). This value was termed the "top count". Top counts were generated using three different normalization methods (40) (Figure 6), and three different filtering statistics (Figure 7). There was substantial correlation in the top count between normalization schemes and filtering statistics (41, 42) used. Thus, while normalization and feature selection methods were important, many genes 15 appeared in the gene lists independently of the method used to pre-process the data. This indicates that the choice of normalization method had only a minimal effect on which genes were selected for use in signature construction. The top count, summed across all normalization methods and statistics, was found to be a robust measure of a gene's differential expression between recurrent and non-recurrent tumours. 20 Genes from the gene lists (see Table 1 and Table 2), were used to generate signatures by random sampling. The generation of samples was weighted, such that genes with higher "top count" were more likely to be selected. A range of signatures was generated, using between 2 and 55 Affymetrix probes. Signatures were selected if 25 they exhibited >80% median classification rate, using three methods of classifiers: k nearest neighbours, with k=1; k-nearest neighbours, with k-3; and support vector machines, with a linear kernel function, and using leave-one-out cross-validation. On average, longer prognostic signatures were preferred over shorter signatures in 30 terms of ability to predict prognosis for new data sets (Figure 4 and Figure 5). The genes FAS and ME2 were also important (discussed, above). These two facts were used, along with the fact that short signatures that do not contain either FAS or ME2 perform less effectively, to select candidate signatures as shown in Table 9, below. Signatures were selected (from the pool of randomly generated signatures) if they 72 WO 2007/073220 PCT/NZ2006/000343 exhibited >80% median classification rate (using three methods of classifiers: k nearest neighbours, with k=l; k-nearest neighbours, with k=3; and support vector machines, with a linear kernel function), using leave-one-out cross-validation. 5 In addition, because, on average, longer signatures (>10 genes/signature) tended to perform better, we selected signatures with 20 or more genes/signatures from a pool of signatures with 30 or more probes/signature. It is expected that these signatures (Table 10) will perform with a classification rate of around 70% when applied to other data sets, on the basis of the results shown in Figures 4 and 5. It was found that all of 10 the signatures generated in this way contained both ME2, and all but one contained FAS, which may be due to the importance of these genes in providing prediction of prognosis. It was noted that the high classification rate obtained using this approach on the in-house data set did not necessarily mean that these signatures that would be expected to perform better than those set forth in Example 12, on other data sets. 15 Rather, the purpose was to produce a range of signatures expected to apply to other data sets as least as well as the previous signatures. The markers comprising the prognostic signatures are set forth in Table 9. 20 Table 9: Additional Prognostic signatures (note SVM=support vector machine, 3NN=3 nearest neighbours, lNN=1 nearest neighbour, Sens=sensitivity, Spec=specificity, for prediction of recurrence) Sinaue Signature Genes (as gene symbols) SVM 3NN INN Sens Spec Sens Spec Sens Spec WARS, STATIC, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, CTSS, MAD2L1, CXCL10, 1 C1QBP, NDUFA9, SLC25A1 1, HNRPD, ME2, 81% 86% 73% 90% 77% 83% CXCL1 1, RBM25, CAMSAP1L1, hCAP-D3, BRRN1, ATP5A1, FAS, FLJ13220, PBK, BRIP1 WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, CDC40, 2 CXCL10, NDUFA9, SLC25A1 1, CA2, ME2, 77% 86% 85% 79% 81% 86% IFT20, TLK1, CXCL1 1, RBM25, AK2, FAS, FLJ13220, PBK, PSATI, STATIC WARS, SFRS2, PRDX3, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL1O, NDUFA9, 3 KPNB1, SLC25A11, CA2, ME2, FUT4, CXCL11, 85% 86% 92% 76% 85% 79% GZMB, RBM25, ATP5A1, CDC42BPA, FAS, RBBP4, HNRPD, BRIP1, STATIC 4 WARS, PRDX3, MTHFD2, PSME2, TES, DCK, 81% 79% 77% 69% 77% 79% 73 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN CDC40, CXCL10, PLK4, NDUFA9, SLC25A11, WHSC1, ME2, CXCL1 1, SLC4A4, RBM25, ATP5A1, CDC42BPA, FAS, BAZIA, AGPAT5, FLJ13220, HNRPD, KLHL24, STATIC HNRPD, WARS, MTHFD2, GMFB, DLGAP4, TYMS, CXCL9, IRF8, GTSE1, RABIF, CXCL10, 5 FAS, TRIM25, KITLG, ClQBP, SLC25A 11, 88% 83% 88% 83% 88% 76% C17orf25, CA2, ME2, SLC4A4, CXCL 11, RBM25, KLHL24, STAT1 HNRPD, WARS, STATIC, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CXCL9, 6 PLK4, KITLG, NDUFA9, ME2, CXCL11, 73% 83% 81% 79% 65% 66% SLC4A4, AK2, FAS, AGPAT5, FLJ13220, PBK, ETNK1 WARS, EIF4E, PRDX3, TK1, GMFB, DLGAP4, TYMS, LMAN1, ARF6, FAS, CHEK1, NDUFA9, 7 SLC25A11, WHSC1, CA2, ME2, CXCL11, IFT20, 88% 90% 88% 90% 85% 86% SLC4A4, RBM25, hCAP-D3, CDC42BPA, FLJ13220, HNRPD, STAT1 WARS, EPAS1, EIF4E, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, 8 CXCL10, C1QBP, NDUFA9, SLC25A11, WHSC1, 77% 86% 85% 79% 77% 79% ME2, TLK1, RBM25, BRRN1, FAS, BRIP1, TRMT5, KLHL24, STAT1 HNRPD, WARS, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CDC40, IRF8, 9 CXCL10, FAS, CHEKI, KITLG, WHSC1, CA2, 69% 79% 85% 83% 77% 79% ME2, TLK1, RBM25, AK2, NUP210, ATP5A1, BRIPI, STATIC HNRPD, EPASI, EIF4E, PRDX3, DLGAP4, TES, CTSS, DCK, CXCL9, CXCL1O, FAS, PLK4, 10 HNRPA3P1, SLC25A1 1, C1QBP, C17orf25, CA2, 85% 79% 85% 79% 77% 72% ME2, RBM25, AK2, SEC1OL1, FLJ13220, TRMT5, STATIC HNRPD, WARS, EIF4E, PRDX3, PSME2, GBP1, GMFB, DLGAP4, TYMS, TES, RABIF, CXCL1O, 11 C1QBP, NDUFA9, SLC25A1 1, C17orf25, ME2, 85% 83% 92% 76% 85% 76% FUT4, CXCL1 1, RBM25, AK2, hCAP-D3, FAS, AGPAT5, SEC1OL1, PBK, STATIC HNRPD, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, DCK, IRF8, NDUFA9, SLC25A11, 12 C17orf25, CA2, ME2, CXCL11, GZMB, RBM25, 88% 79% 92% 69% 92% 83% NUP210, SOCS6, DDAH2, FAS, RBBP4, MARCH, SEC10L1, KLHL24, STATIC WARS, EPASI, STATIC, MTHFD2, MCM6, 13 GBP1, GMFB, DLGAP4, TYMS, ARF6, CXCL10, 88% 90% 88% 76% 77% 69% FAS, KITLG, NDUFA9, CA2, ME2, GZMB, CXCL1 1, RBM25, RBBP4, PBK, PSAT1, HNRPD WARS, EPAS1, EIF4E, PRDX3, PSME2, GBP1, TK1, GMFB, TYMS, CXCL9, FAS, CHEKI, 14 SLC25A11, NDUFA9, WHSC1, CA2, ME2, FUT4, 85% 83% 92% 76% 92% 79% CXCL11, RBM25, CAMSAP1L1, SFRS2, DDAH2, AGPAT5, HNRPD, BRIPI, ETNK1 SFRS2, EIF4E, PRDX3, MTHFD2, MCM6, TK1, 15 GMFB, TYMS, TES, CTSS, ARF6, CXCL9, 81% 83% 81% 83% 77% 79% RABIF, CXCL10, FAS, KITLG, SLC25A11, ME2, 74 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN IFT20, SLC4A4, CXCL 11, RBM25, PSAT1, HNRPD, TRMT5, STAT1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, TYMS, LMAN1, CDC40, CXCL9, CXCL10, PLK4, 16 CHEKI, SLC25A11, C1QBP, NDUFA9, ME2, 92% 93% 81% 83% 81% 83% IFT20, SLC4A4, CXCL1 1, RBM25, DDAH2, FAS, HNRPD, BRIP1, STATIC WARS, EIF4E, GMFB, DLGAP4, TYMS, CTSS, MAD2L1, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, 17 TRJM25, KPNB1, SLC25A11, HNRPD, ME2, 92% 90% 85% 79% 81% 76% CXCL1 1, RBM25, AK2, hCAP-D3, DDAH2, SEC1OL1, ETNK1, STAT1 HNRPD, WARS, SFRS2, MTHFD2, PSME2, TK1, GMFB, DLGAP4, ARF6, CXCL10, TRIM25, 18 NDUFA9, SLC25A11, WHSC1, ME2, CXCL11, 81% 79% 85% 90% 81% 93% TLK1, RBM25, CAMSAP1L1, hCAP-D3, CDC42BPA, FAS, AGPAT5, STAT1 HNRPD, WARS, SFRS2, STATIC, EIF4E, PSME2, TYMS, USP4, DCK, ARF6, CXCL9, RABEF, 19 CXCL10, C1QBP, SLC25A11, ME2, IFT20, 96% 86% 73% 76% 73% 66% SLC4A4, CXCL1 1, RBM25, AK2, SOCS6, FAS, ETNK1 WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, TES, ARF6, CXCL10, FAS, 20 KITLG, C1QBP, SLC25A11, C17orf25, ME2, 77% 79% 73% 83% 81% 86% FUT4, CXCL1 1, RBM25, ATP5A1, FLJ13220, PSATI, HNRPD, STATIC WARS, PSME2, GMFB, DLGAP4, USP4, ARF6, CDC40, CXCL9, IRF8, RABIF, CXCL1O, PLK4, 21 KITLG, C1QBP, NDUFA9, SLC25A11, WHSC1 C17orf25, ME2, TLK1, SLC4A4, RBM25, hCAP- 77% 72% 85% 83% 85% 79% D3, SOCS6, FAS, AGPAT5, SEC10L1, KLHL24, STAT1 WARS, MTH{FD2, PSME2, GBP1, TK1, GMFB, DLGAP4, CXCL9, CXCL10, CHEK1, TRIM25, 22 SLC25A11, C17orf25, HNRPD, ME2, SLC4A4, 77% 79% 77% 76% 81% 72% RBM25, AK2, BRRN1, FAS, DKFZp762E1312, SECIOL1, PBK, TRMT5, STAT1 HNRPD, WARS, STATIC, EIF4E, PRDX3, DLGAP4, TYMS, ARF6, CXCL9, CXCL1O, FAS, 23 HNRPA3PI, C1QBP, NDUFA9, SLC25A1 1, 85% 83% 92% 90% 85% 76% WHSC1, ME2, CXCL1 1, RBM25, MARCH5, SEC 1OL1, BRIPI WARS, PRDX3, PSME2, GMFB, DLGAP4, CTSS, LMAN1, CXCL9, CXCL1O, HNRPA3P1, 24 SLC25A11, NDUFA9, C17orf25, ME2, FUT4, 85% 83% 77% 69% 81% 69% SLC4A4, RBM25, AK2, FAS, MARCH, PBK, HNRPD, KLHL24, ETNK1, STATIC WARS, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CDC40, CXCL9, 25 CXCL10, TRIM25, NDUFA9, CA2, ME2, TLK1, 81% 83% 77% 83% 81% 72% CXCL1 1, SLC4A4, RBM25, AK2, ATP5A1, SOCS6, DDAH2, FAS, MARCH, PBK, STATIC WARS, EIF4E, MTHFD2, PSME2, GMFB, 26 DLGAP4, TYMS, ARF6, CXCL1O, PLK4, CHEK1, 81% 83% 92% 86% 81% 79% HNRPA3P1, C1QBP, NDUFA9, SLC25A1 1, 75 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN WHSC1, CA2, ME2, CXCL11, RBM25, CAMSAP1L1, FAS, SEC10L1, FLJ13220, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, TYMS, LMAN1, CDC40, CXCL1O, ClQBP, 27 NDUFA9, KPNB1, CA2, ME2, GZMB, TLK1, 85% 90% 85% 86% 81% 79% SLC4A4, RBM25, ATP5A1, FAS, AGPAT5, SEC1OL1, FLJ13220, HNRPD, STATIC HNRPD, WARS, EPASI, MTHFD2, PSME2, TK1, TYMS, CXCL9, CXCL10, FAS, TRIM25, 28 KITLG,C1QBP,NDUFA9,CA2,ME2,CXCL11, 88% 86% 81% 86% 81% 76% RBM25, AK2, BRRN1, FLJ10534, SEC1OL1, PBK, ETNK1, STATIC E1F4E, PRDX3, PSME2, DLGAP4, CTSS, CXCL9, GTSE1, CXCL10, FAS, PLK4, KITLG, 29 SLC25A11, CA2, ME2, GZMB, CXCL11, RBM25, 88% 86% 88% 76% 77% 69% AK2, AGPAT5, MARCH5, FLJ13220, PBK, HNRPD, STAT1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, CTSS, CDC40, CXCL9, 30 CXCL1O, FAS, PLK4, NDUFA9, ME2, CXCL11, 77% 79% 81% 79% 65% 69% RBM25, AK2, BRRN1, RBBP4, HNRPD, KLHL24, ETNK1, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, CDC40, CXCL9, 31 TRIM25, SLC25A11, CA2, ME2, IFT20, CXCL11, 85% 83% 92% 76% 92% 72% RBM25, BRRN1, CDC42BPA, FAS, AGPAT5, FLJ10534, HNRPD, TRMTS, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, 32 CTSS, DCK, CXCL9, CXCL1O, FAS, KITLG, 85% 79% 77% 83% 77% 72% NDUFA9, ME2, CXCL1 1, RBM25, ATP5A1, PBK, ETNK1, STATIC WARS, SFRS2, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, LMAN1, CDC40, 33 SLC4A4, CXCL10, FAS, CHEK1, SLC25A1 1, 73% 79% 92% 90% 88% 79% C1QBP, WHSC1, C17orf25, CA2, ME2, RBM25, SOCS6, AGPAT5, HNRPD, STAT1 HNRPD, WARS, MTHFD2, PSME2, GMFB, DLGAP4, RABIF, CXCL1O, TRIM25, KITLG, 34 C1QBP, KPNB1, SLC25A11, WHSC1, ME2, 85% 86% 92% 90% 81% 86% RBM25, CAMSAP1L1, BRRN1, CDC42BPA, FAS, AGPAT5, SEC1OL1, ETNK1, STATIC HNRPD, WARS, SFRS2, SFPQ, MTHFD2, DLGAP4, TYMS, USP4, LMAN1, ARF6, CDC40, 35 C1QBP, C17orf25, CA2, ME2, CXCL11, SLC4A4, 81% 83% 85% 79% 73% 79% RBM25, AK2, ATP5A1, FAS, SEC10L1, FLJ13220, ETNK1, STATIC WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, LMAN1, ARF6, 36 MAD2L1, GTSEl, CXCL1O, FAS, KITLG, 85% 83% 85% 90% 88% 90% SLC25A1 1, WHSC1, ME2, FUT4, IFT20, RBM25, AGPAT5, HNRPD, STAT1 WARS, SFRS2, EIF4E, MTHFD2, TK1, GMFB, 37 DLGAP4, TYMS, LMAN1, CXCL1O, CHEK1, 73% 79% 92% 83% 85% 86% HNRPA3P1, C1QBP, NDUFA9, SLC25A11, M2, CXCL11, RBM25, BRRN1, CDC42BPA, FAS, 76 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN SEC1OL1, PSAT1, HNRPD, KLHL24, STATIC WARS, EPAS1, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, CTSS, LMAN1, DCK, 38 CDC40, RABIF, CXCL10, HNRPA3P1, C1QBP, 85% 86% 77% 90% 85% 90% C17orf25, ME2, CXCL11, TLK1, RBM25, FAS, FLJ13220, HNRPD, KLHL24, STATIC WARS, SFRS2, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, CTSS, SLC4A4, 39 CXCL10, SLC25A1 1, C17orf25, HNRPD, ME2, 88% 83% 88% 79% 85% 72% CXCL11, RBM25, AK2, CDC42BPA, FAS, AGPAT5, SEC1OL1, TRMT5, STATIC SFRS2, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, CXCL9, IRF8, RABIF, 40 CXCL10, FAS, TRIM25, SLC25A11, NDUFA9, 85% 93% 88% 83% 81% 69% ME2, CXCL 11, RBM25, AGPAT5, FLJ13220, HNRPD, BRIP1, ETNK1, STAT1 HNRPD, WARS, EIF4E, PRDX3, TK1, DLGAP4, TYMS, CDC40, CXCL9, GTSE1, CXCL10, FAS, 41 KITLG, SLC25A11, NDUFA9, ME2, IFT20, 85% 83% 96% 79% 92% 72% SLC4A4, RBM25, NUP210, BAZ1A, SEC10L1, TRMT5, KLHL24, STAT1 WARS, SFRS2, EIF4E, PRDX3, PSME2, DLGAP4, TYMS, CTSS, CXCL9, IRF8, CXCL1O, 42 FAS, C1QBP, NDUFA9, KPNB1, SLC25A1 1, 81% 79% 85% 83% 92% 69% ME2, SLC4A4, RBM25, SOCS6, MARCH, SEC1OL1, HNRPD, BRIPI, STATIC WARS, EPASI, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, CDC40, CXCL9, 43 CXCL1O, SLC25A11, C1QBP, WHSCI, ME2, 77% 83% 88% 62% 92% 72% GZMB, RBM25, SFRS2, FAS, AGPAT5, SEC10LI, PSATI, KLHL24, ETNK1, STATIC WARS, PSME2, GMFB, DLGAP4, TYMS, CDC40, CXCL1O, FAS, PLK4, C1QBP, NDUFA9, 44 SLC25A11, CA2, ME2, CXCL11, IFT20, TLK1, 85% 86% 96% 79% 81% 83% RBM25, NUP210, BAZ1A, MARCH, PSATI, TRMT5, STAT1 WARS, PRDX3, MTHFD2, PSME2, TYMS, CXCL1O, FAS, CHEKI, TRIM25, C1QBP, 45 NDUFA9, C17orf25, CA2, ME2, CXCL11, IFT20, 88% 90% 85% 79% 88% 66% RBBP4, RBM25, AK2, CDC42BPA, AGPAT5, DKFZp762E1312, HNRPD, STATIC WARS, SFRS2, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, USP4, CDC40, CXCL1O, FAS, HNRPA3P1, KITLG, NDUFA9, 46 KPNB1, SLC25A11, WHSC1, CA2, ME2-, 81% 79% 81% 79% 77% 72% CXCL11, SLC4A4, RBM25, hCAP-D3, BRRN1, CDC42BPA, AGPAT5, MARCH, SECIOL1, FLJ13220, BRIP1, ETNK1, STATIC HNRPD, WARS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CTSS, MAD2L1, CDC40, CXCL9, CXCL10, KITLG, 47 NDUFA9, SLC25A11, WHSCI, C17orf25, CA2, 81% 83% 88% 86% 88% 69% ME2, SLC4A4, CXCL1 1, RBM25, AK2, ATP5A1, CDC42BPA, FAS, BAZIA, AGPAT5, SEC1OL1, BRIP1, TRMT5, STAT1 48 WARS, EIF4E, SFPQ, PRDX3, MTHFD2, 77% 83% 81% 79% 73% 69% 77 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN PSME2, GMFB, DLGAP4, TYMS, USP4, ARF6, CXCL9, CXCL1O, FAS, HNRPA3P1, C1QBP, NDUFA9, KPNB1, SLC25A1 1, ME2, CXCL1 1, IFT20, TLK1, RBM25, RBBP4, AGPAT5, MARCH5, SEC10L1, PBK, PSATI, HNRPD, BRIPI, STATIC HNRPD, WARS, SFRS2, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, DCK, ARF6, CXCL9, CXCL10 77% 83% 77% 79% 81% 83% 4NRPA3P1, C1QBP, NDUFA9, SLC25A11, ME2, CXCLI 1, IFT20, TLK1, RBM25, AK2, hCAP-D3, ATP5A1, FAS, MARCH5, KLHL24, STATIC WARS, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, TKI, GMFB, DLGAP4, TYMS, CTSS, CXCL9, - IRF8, CXCLIO, PLK4, TRIM25, ClQBP, NDUFA9, SLC25A11, C17orf25, ME2, SLC4A4, 81% 79% 85% 83% 77% 66% AK2, CAMSAP1L1, FAS, BAZIA, MARCH5, FLJ13220, PBK, BRIPI, KLHL24, ETNK1 HNRPD, WARS, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, TES, ARF6, CXCL9, 51 CXCL1O, TRIM25, SLC25A1 1, NDUFA9, WHSC1, CA2, ME2, SLC4A4, CXCL11, RBM25, 79% 85% 79% 85% 72% hCAP-D3, ATP5A1, FAS, RBBP4, SEC10L1, FLJ13220, PBK, BRIPI, KLHL24, ETNK1, STATIC WARS, EPAS1, STAT1, EIF4E, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, CXCL1O, FAS, HNRPA3P1, 52 SLC25A11, C1QBP, ME2, FUT4, CXCL11, 77% 83% 81% 86% 69% 76% SLC4A4, RBM25, AK2, CAMSAP1L1, SFRS2, DDAH2, RBBP4, AGPAT5, FLJ10534, DKFZp762E1312, PSATI, HNRPD HNRPD, WARS, SFRS2, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, GTSE1, FAS, 53 HNRPA3P1, SLC25A11, NDUFA9, KPNB1, CA2, 88% 83% 92% 79% 92% 72% ME2, CXCL1 1, SLC4A4, RBM25, BRRN1, CDC42BPA, RBBP4, BAZ1A, SEClOL1, BRIPi, KLHL24, STAT 1 HNRPD, WARS, EPASI, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, LMAN1, MAD2L1, CDC40, SLC4A4, CXCL9, CXCL1O, FAS, KITLG, C1QBP, 77% 79% 85% 83% 85% 79% SLC25A1 1, ME2, CXCL1 1, RBM25, AK2, CDC42BPA, SFRS2, SEC1OL1, STATIC WARS, EPASI, STAT1, EIF4E, SFPQ, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CXCL9, IRF8, CXCL1O, FAS, NDUFA9, C17orf25, CA2, HNRPD, ME2, CXCL11, IFT20, 88% 90% 88% 76% 88% 79% RBM25, CDC42BPA, FLJ10534, SEC1OL1, PBK, BRIPI, TRMT5 SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, LMAN1, SLC4A4, CXCL9, CXCL10, FAS, PLK4, TRIM25, 56 SLC25A11, NDUFA9, WHSCI, C17orf25, ME2, 85% 79% 85% 79% 81% 86% FUT4, CXCL1 1, IFT20, RBM25, ATP5A1, CDC42BPA, FLJ10534, SEC10L1, HNRPD, KLHL24, STAT1 78 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN iNN SFRS2, PAICS, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, CTSS, LMAN1, SLC4A4, CXCL9, IRF8, CXCL1O, TRIM25, NDUFA9, C17orf25, CA2, HNRPD, 81 86% 85% 79% 85% 83% ME2, CXCL11, IFT20, RBM25, AK2, ATP5A1, FAS, PBK, BRIPI, TRMT5, ETNK1, STATIC HNRPD, WARS, SFRS2, STATIC, EIF4E, MTHFD2, PSME2, DLGAP4, TYMS, DCK, CDC40, CXCL9, IRF8, CXCL10, PLK4, 58 SLC25A1 1, NDUFA9, KPNB1, WHSC1, 81% 76% 92% 79% 88% 72% C17orf25, CA2, ME2, NUP210, SOCS6, CDC42BPA, FAS, AGPAT5, SEC1OL1, FLJ13220, BRIPI, KLHL24, ETNK1 WARS, SFRS2, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CDC40, CXCL9, GTSE1, CXCL 10, FAS, PLK4, TRIM25, SLC25A11, 59 C1QBP, NDUFA9, KPNB1, WHSC1, C17orf25, 81% 79% 88% 86% 85% 83% CA2, ME2, CXCL1 1, TLK1, RBM25, BRRN1, AGPAT5, MARCH5, HNRPD, BRIPI, TRMT5, KLHL24, STATIC HNRPD, WARS, SFRS2, EIF4E, SFPQ, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, 60 CXCL10, FAS, CHEK1, C1QBP, NDUFA9, 92% 79% 77% 86% 69% 76% SLC25A11, WHSCI, ME2, TLK1, CXCL11, RBM25, CDC42BPA, AGPAT5, FLJ10534, FLJ13220, PSATI, STATIC WARS, EPAS1, EIF4E, MTHFD2, PSME2, GMIFB, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, CXCL10, FAS, PLK4, TRIM25, 61 C1QBP, C17orf25, CA2, ME2, CXCL11, SLC4A4, 77% 83% 85% 72% 85% 69% RBM25, AK2, ATP5A1, CDC42BPA, AGPAT5, FLJ10534, DKFZp762E1312, SEC1OL1, PBK, PSAT1, STATIC HNRPD, WARS, STATIC, EIF4E, SFPQ, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CXCL9, GTSE1, CXCL10, FAS, CHEKI, C1QBP, 62 NDUFA9, SLC25A1 1, WHSCI, C17orf25, CA2, 85% 76% 88% 83% 77% 69% ME2, CXCL1 1, SLC4A4, RBM25, CDC42BPA, DDAH2, AGPAT5, FLJ13220, PBK, TRMT5, KLHL24, ETNK1 WARS, EIF4E, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, MAD2L1, CXCL10, TRI425, C1QBP, NDUFA9, SLC25A11, 63 C17orf25, HNRPD, ME2, CXCL11, IFT20, 81% 83% 65% 83% 73% 72% RBBP4, TLK1, SLC4A4, RBM25, AK2, CAMSAP1L1, SOCS6, FAS, FLJ10534, FLJ13220, PBK, BRIPI, ETNK1, STATIC WARS, SFRS2, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, CXCL9, IRF8, RABIF, CXCLIO, CHEKI, 64 NDUFA9, ME2, FUT4, CXCL1 1, SLC4A4, 69% 79% 73% 83% 85% 83% RBM25, AK2, CAMSAP1L1, FAS, RBBP4, MARCH, SEC1OL1, PBK, PSAT1, HNRPD, TRMT5, KLHL24, STAT1 65 HNRPD, WARS, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, CTSS, LMAN1, ARF6, CDC40, 85% 72% 88% 79% 77% 72% 79 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN SLC4A4, CXCL9, CXCL1O, FAS, CHEK1, KITLG, C1QBP, NDUFA9, SLC25A1 1, WHSC1, ME2, FUT4, GZMB, IFT2o, RBM25, CAMSAP1L1, BAZ1A, AGPAT5, SEC10L1, PBK, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, STATIC, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, ARF6, IRF8, RABIF, CXCL10, PLK4, 66 HNRPA3P1, SLC25A11, C1QBP, CA2, ME2, 81% 76% 96% 69% 81% 66% GZMB, CXCL1 1, RBM25, NUP210, ATP5A1, DDAH2, FAS, PSAT1, BRIP1, TRMT5, KLHL24, ETNK1 WARS, EPASI, STAT1, EIF4E, SFPQ, PSME2, GMFB, DLGAP4, TYMS, CTSS, DCK, SLC4A4, 67 CXCL9, CXCL10, C1QBP, NDUFA9, SLC25A11, 77% 83% 92% 79% 77% 69% C17orf25, CA2, ME2, FUT4, CXCL1 1, RBM25, AK2, NUP210, CAMSAP1L1, FAS, AGPAT5, FLJ13220, PBK, HNRPD, ETNK1 HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, GMFB, TYMS, TES, CDC40, SLC4A4, 68 CXCL9, CXCL10, PLK4, HNRPA3P1, SLC25AI 1, 76% 88% 79% 92% 79% C1QBP, NDUFA9, C17orf25, CA2, ME2, CXCL11, RBM25, NUP210, hCAP-D3, SOCS6, FAS, SEC1OLI, PBK, TRMT5, KLHL24, STAT1 HNRPD, WARS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, TES, 69 CTSS, CXCL9, CXCL1O, FAS, CHEKI, C1QBP 81% 83% 92% 72% 77% 79% NDUFA9, SLC25A1l, CA2, ME2, GZMB, TLK1, CXCL1 1, RBM25, BRRN1, MARCH, FLJ13220, PBK, TRMT5, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, USP4, 70 TES, LMAN1, CDC40, CXCL9, IRF8, CXCL1O, 81% 79% 85% 83% 85% 79% KITLG, NDUFA9, SLC25A1 1, WHSC1, CA2, ME2, CXCL1 1, RBM25, AK2, CAMSAP1L1, FAS, SEC1OL1, PBK, BRIP1, TRMT5, STAT1 HNRPD, WARS, PAICS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, 71 CXCL9, CXCL10, FAS, TRIM25, C1QBP, SLC25A11, C17orf25, CA2, ME2, CXCL11, 85% 86% 88% 76% 81% 72% IFT20, RBBP4, RBM25, AK2, hCAP-D3, ATP5A1, BAZIA, PBK, BRIPI, KLHL24, ETNK1, STATIC WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, TYMS, USP4, CXCL9, GTSEl, RABIF, CXCL1O, FAS, PLK4, CHEKI, 72 SLC25A11, C1QBP, NDUFA9, C17orf25, CA2, 81% 83% 85% 86% 88% 83% ME2, FUT4, IFT20, RBBP4, SLC4A4, CXCL11, RBM25, hCAP-D3, FLJ10534, MARCH5, HNRPD, TRMT5, STAT1 HNRPD, WARS, EIF4E, PRDX3, PSME2, TK1, DLGAP4, TYMS, CTSS, LMAN1, ARF6, CXCL9, CXCL10, CHEKI, TRIM25, NDUFA9, KPNB1, 73 SLC25A11, WHSC1, ME2, SLC4A4, RBM25, 73% 79% 81% 79% 77% 76% AK2, SFRS2, DDAH2, FAS, FLJ10534, MARCH5, FLJ13220, BRIP, TRMT5, KLHL24, ETNK1, STAT1 74 WARS, SFRS2, EIF4E, MTHFD2, PSME2, 92% 86% 81% 83% 88% 76% 80 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN DLGAP4, TYMS, USP4, TES, MAD2L1, SLC4A4, CXCL9, CXCLIO, CHEKI, HNRPA3P1, TRIM25, NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, ME2, IFT20, TLK1, CXCL11, RBM25, BRRN1, ATP5A1, FAS, AGPAT5, PBK, HNRPD, ETNK1, STAT1 HNRPD, WARS, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, LMAN1, CDC40, GTSEl, CXCL1O, FAS, KITLG, C1QBP, NDUFA9, 75 SLC25A11, CA2, ME2, CXCL11, GZMB, IFT20, 85% 86% 88% 79% 85% 76% TLK1, SLC4A4, RBM25, hCAP-D3, BRRN1, DDAH2, MARCH5, FLJ13220, PBK, BRIP1, KLHL24, STATIC HNRPD, WARS, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, CDC40, SLC4A4, IRF8, GTSE1, 76 CXCL1O, CHEK1, HNRPA3P1, TRIM25, 85% 83% 88% 86% 85% 83% NDUFA9, WHSC1, CA2, ME2, CXCL1 1, RBM25, NUP210, ATP5A1, CDC42BPA, SFRS2, FAS, MARCH5, SEC10L1, BRIPI, STAT1 HNRPD, WARS, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, SLC4A4, CXCL1O, PLK4, CHEKI, 77 HNRPA3P1, KPNB1, SLC25A11, WHSC1, 96% 83% 92% 83% 88% 79% C17orf25, CA2, ME2, CXCL 11, IFT20, RBBP4, TLK1, RBM25, CDC42BPA, SFRS2, FAS, AGPAT5, FLJ10534, SECIOL1, TRMT5, STATIC WARS, SFRS2, STATIC, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, MAD2L1, SLC4A4, CXCL9, CXCL10, 78 SLC25A1 1, C17orf25, CA2, ME2, FUT4, GZMB, 81% 83% 92% 76% 85% 76% CXCL1 1, RBM25, CAMSAPiL1, BRRN1, CDC42BPA, FAS, FLJ10534, SEC1OL1, PBK, TRMT5, KLHL24 HNRPD, WARS, SFRS2, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CXCL9, CXCL10, FAS, KITLG, C1QBP, 79 NDUFA9, C17orf25, CA2, ME2, RBM25, SOCS6, 81% 72% 88% 79% 88% 69% CDC42BPA, BAZiA, AGPAT5, DKFZp762E1312, SEC10L1, FLJ13220, PSAT1, BRIPI, TRMT5, KLHL24, STAT1 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, DLGAP4, TYMS, TES, CTSS, ARF6, CXCL9, CXCL1O, FAS, HNRPA3P1, 80 TRIM25, SLC25A11, C1QBP, NDUFA9, HNRPD, 85% 86% 81% 69% 69% 69% ME2, CXCL1 1, RBBP4, RBM25, AK2, AGPAT5, FLJ10534, DKFZp762E1312, SECIOLI, PBK, KLHL24, STAT1 EIF4E, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, CXCL9, CXCLIO, FAS, PLK4, NDUFA9, WHSC1, C17orf25, CA2, 81 HNRPD, ME2, IFT20, RBM25, NUP210, 81% 79% 85% 76% 81% 66% CDC42BPA, DDAH2, BAZIA, AGPAT5, FLJ10534, DKFZp762E1312, SEC10L1, FLJ13220, PBK, BRIPI, TRMT5, STATIC 82 WARS, SFRS2, STATi, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, 81% 90% 85% 76% 85% 72% 81 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN LMAN1, DCK, CDC40, CXCL9, CXCL1O, FAS, TRIM25, C1QBP, NDUFA9, SLC25A1 1, CA2, ME2, CXCL1 1, SLC4A4, RBM25, AK2, BRRN1, AGPAT5, DKFZp762E1312, FLJ13220, PBK SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, LMAN1, ARF6, CDC40, IRF8, CXCL10, 83 CHEKI, C1QBP, SLC25A11, WHSCI, ME2, 65% 79% 77% 83% 77% 79% SLC4A4, CXCL1 1, RBM25, NUP2 10, FAS, FLJ10534, MARCH, FLJ13220, PSAT1, HNRPD, BRIP1, TRMT5, KLHL24 HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, 84 TYMS, CTSS, ARF6, MAD2L1, CXCL1O, TRIM25, KITLG, NDUFA9, WHSC1, CA2, ME2, 85% 83% 88% 76% 73% 72% GZMB, IFT20, CXCL11, RBM25, FAS, AGPAT5, MARCH, PSATI, BRIPI, TRMTS, STATIC HNRPD, SFRS2, STAT1, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, USP4, CTSS, ARF6, SLC4A4, CXCL9, RABIF, CXCL10, FAS, 85 TRIM25, KITLG, C1QBP, SLC25A11, WHSCI, 88% 76% 92% 76% 81% 69% CA2, ME2, GZMB, RBBP4, CXCL1 1, RBM25, AGPAT5, MARCH, SEC1OL1, PBK, BRIP1, TRMT5 WARS, STAT1, EIF4E, MTHFD2, PSME2, DLGAP4, TYMS, USP4, LMAN1, CDC40, CXCL9, IRF8, CXCL 10, PLK4, TRIM25, C1QBP, 86 NDUFA9, SLC25A11, CA2, ME2, CXCL11, 85% 76% 81% 83% 81% 76% RBM25, ATP5A1, SFRS2, FAS, AGPAT5, MARCH, FLJ13220, PBK, HNRPD, BRIPI, TRMT5, KLHL24, ETNK1 HNRPD, WARS, EPAS1, STATIC, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, SLC4A4, CXCL9, IRF8, GTSE1, 87 RABIF, CXCL1O, FAS, PLK4, HNRPA3P1, TRIM25, SLC25A11, C1QBP, NDUFA9, WHSCI, 7 79% 88% 83% 69% 72% ME2, CXCL1 1, TLK1, RBM25, AK2, NUP210, BRRN1, ATP5A1, SFRS2, AGPAT5, FLJ10534, MARCH5, PSAT1, BRIPI, KLHL24 WARS, SFRS2, EPASI, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, MAD2L1, CDC40, CXCL9, 88 IRF8, CXCL1O, FAS, CHEKI, NDUFA9, KPNB1, 73% 83% 85% 79% 81% 72% SLC25A11, WHSCI, C17orf25, CA2, ME2, CXCL11, IFT20, SLC4A4, RBM25, CDC42BPA, BAZ1A, AGPAT5, MARCH, PBK, PSATI, HNRPD, BRIPI, TRMT5, ETNK1 HNRPD, WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, TYMS, USP4, CTSS, DCK, CDC40, SLC4A4, CXCL9, CXCL10, FAS, 89 CHEKI, SLC25A11, C1QBP, NDUFA9, WHSCI, 77% 76% 88% 79% 85% 66% CA2, ME2, GZMB, RBBP4, RBM25, ATP5A1, SOCS6, AGPAT5, MARCH, DKFZp762E1312, SEC1OL1, PBK, BRIPI, TRMT5, KLHL24 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, 90 PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, 77% 79% 88% 76% 88% 76% CTSS, SLC4A4, CXCL9, IRF8, GTSE1, CXCL10, 82 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN PLK4, CHEK1, HNRPA3P1, KITLG, SLC25A1 1, CIQBP, NDUFA9, C17orf25, CA2, IE2, GZMB, CXCL11, RBM25, AK2, SOCS6, DDAH2, FAS, RBBP4, FLJ10534, MARCH5, DKFZp762E1312, PBK, HNRPD, BRIPI, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPASI, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, DCK, ARF6, 91 MAD2L1, CDC40, SLC4A4, CXCL9, RABIF, 69% 83% 81% 79% 77% 76% CXCL1O, FAS, SLC25A1 1, C1QBP, NDUFA9, WHSC1, C17orf25, ME2, FUT4, CXCL11, IFT20, RBBP4, RBM25, CAMSAP1L1, SEC10L1, PBK, PSATI, KLHL24 HNRPD, WARS, STAT1, ELF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, MAD2L1, SLC4A4, CXCL9, CXCL1O, 92 FAS, CHEK1, HNRPA3P1, SLC25A11, C1QBP, 77% 83% 92% 83% 77% 66% NDUFA9, WHSC1, CA2, ME2, GZMB, CXCL11, RBM25, AK2, CAMSAP1L1, DDAH2, BAZIA, AGPAT5, SEC10L1, FLJ13220, PBK, BRIPI, TRMT5 HNRPD, WARS, SFRS2, EPASI, STATIC, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, DCK, MAD2L1, CDC40, RABIF, CXCL10, FAS, PLK4, KITLG, SLC25A1 1, NDUFA9, WHSC1, CA2, ME2, CXCL1 1, IFT20, TLKI1, 73% 83% 77% 79% 77% 76% RBM25, CDC42BPA, DDAH2, RBBP4, MARCH5, DKFZp762E1312, PBK, PSATI, BRIPI, KLHL24, ETNKI HNRPD, WARS, STAT1, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, DCK, ARF6, CDC40, CXCL9, IRF8, RABIF, CXCL1O, FAS, IHNRPA3P1, TRIM25, SLC25A 11, NDUFA9, 88% 83% 85% 76% 85% 69% WHSC1, CA2, ME2, CXCL1 1, GZMB, IFT20, SLC4A4, SFRS2, AGPAT5, FLJ10534, MARCH5, PBK, BRIP1 WARS, SFRS2, STAT1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, DCK, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, CXCL10, FAS, C1QBP, NDUFA9, 73% 79% 85% 83% 85% 79% WHSC1, CA2, ME2, CXCL1 1, IFT20, RBM25, hCAP-D3, ATP5A1, DDAH2, FLJ10534, MARCH5, DKFZp762E1312, SEC1OL1, PBK, HNRPD, BRIPI, TRMT5, KLHL24 HNRPD, WARS, SFRS2, EPASI, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, ARF6, CXCL9, CXCL1O, 96 FAS, PLK4, CHEKI, HNRPA3P1, SLC25A1 1, 85% 86% 92% 76% 77% 69% C1QBP, WHSC1, CA2, ME2, CXCL1 1, GZMB, IFT20, RBM25, NUP210, SOCS6, AGPAT5, MARCH5, SEClOL1, PBK, BRIPI, ETNK1 HNRPD, WARS, SFRS2, EPAS1, STATIC, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, 97 TYMS, TES, DCK, CDC40, SLC4A4, CXCL9, 92% 90% 88% 76% 77% 66% CXCL10, FAS, TRIM25, NDUFA9, SLC25A1 1, WHSC1, CA2, ME2, GZMB, IFT20, TLK1, 83 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN CXCL1 1, RBM25, AK2, hCAP-D3, BRRN1, AGPAT5, MARCH5, FLJ13220, TRMT5, KLHL24 HNRPD, WARS, EIF4E, SFPQ, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, DCK, CDC40, SLC4A4, CXCL9, GTSE1, CXCL1O, FAS, 98 PLK4, CHEKI, KITLG, SLC25A1 1, C1QBP, 73% 76% 92% 83% 81% 83% NDUFA9, KPNB1, WHSC1, C17orf25, CA2, ME2, CXCL11, TLK1, RBM25, NUP210, RBBP4, AGPAT5, MARCH5, SEC10L1, FLJ13220, PBK, TRMT5, KLHL24, ETNK1, STATIC WARS, EPAS1, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, USP4, CTSS, CDC40, SLC4A4, CXCL9, IRF8, RABIF, CXCL10, FAS, HNRPA3P1, TRIM25, SLC25A11, NDUFA9, 99 WHSC1, C17orf25, HNRPD, ME2, FUT4, 85% 86% 92% 72% 77% 69% CXCL11, GZMB, RBM25, AK2, ATP5A1, CDC42BPA, SFRS2, BAZ1A, AGPAT5, MARCH5, FLJ13220, BRIPI, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, PAICS, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, ARF6, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, GTSE1, CXCL1O, 100 HNRPA3P1, SLC25A1 1, C1QBP, NDUFA9, 77% 79% 88% 83% 88% 76% WHSC1, C17orf25, CA2, ME2, CXCL 11, RBM25, hCAP-D3, CDC42BPA, FAS, AGPAT5, FLJ10534, MARCH5, DKFZp762E1312, SEC10L1, PBK, BRIP1, TRMT5, ETNK1, STAT1 HNRPD, WARS, STATIC, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, ARF6, CXCL9, IRF8, CXCL 10, FAS, 101 PLK4, HNRPA3P1, TRIM25, ClQBP, NDUFA9, 73% 83% 88% 86% 85% 76% SLC25A11, WHSC1, C17orf25, ME2, CXCL11, IFT20, RBBP4, TLK1, SLC4A4, RBM25, AK2, NUP210, CAMSAP1L1, DDAH2, AGPATS, MARCH5, SEC1OL1, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, USP4, CTSS, ARF6, CDC40, CXCL10, FAS, PLK4, 102 TRIM25, KITLG, SLC25A11, C1QBP, NDUFA9 WHSC1, C17orf25, CA2, ME2, IFT20, RBBP4, 85% 86% 81% 83% 85% 79% TLK1, SLC4A4, CXCL1 1, RBM25, AK2, BAZIA, MARCH5, SEC1OL1, FLJ13220, PBK, BRIPI, KLHL24, STAT1 WARS, SFRS2, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, SLC4A4, CXCL9, CXCL10, 103 FAS, PLK4, TRJM25, C1QBP, NDUFA9, SLC25A11, WHSC1, CA2, HNRPD, ME2, GZMB, 81% 86% 85% 76% 77% 76% IFT20, TLK1, CXCL11, RBM25, RBBP4, MARCH, PBK, PSATI, BRIPI, TRMT5, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, 104 LMAN1, ARF6, CDC40, CXCL9, GTSE1, 85% 86% 88% 72% 77% 72% CXCL10, FAS, CHEK1, HNRPA3P1, SLC25A11, C1QBP, WHSC1, CA2, ME2, GZMB, IFT20, 84 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN iNN SLC4A4, CXCL11, RBM25, BAZ1A, AGPAT5, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, TRMT5, ETNK1, STAT1 WARS, PAICS, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, CTSS, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, RABIF, CXCL1O, FAS, CHEK1, HNRPA3P1, 105 TRIM25, NDUFA9, SLC25A11, CA2, HNRPD, 88% 86% 81% 83% 81% 83% ME2, CXCLI 1, IFT20, RBM25, AK2, CAMSAP1L1, BRRN1, SFRS2, DDAH2, RBBP4, SEC1OL1, PBK, PSATI, BRIPI, TRMT5, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, DCK, SLC4A4, CXCL9, 106 CXCL10, PLK4, HNRPA3P1, C1QBP, NDUFA9, 81% 90% 85% 83% 81% 76% SLC25A11, WHSC1, C17orf25, CA2, ME2, CXCL1 1, GZMB, IFT20, RBBP4, TLK1, RBM25, CAMSAP1L1, FAS, MARCH5, DKFZp762E1312, SEC1OL1, PBK, STAT1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, MAD2L1, CDC40, SLC4A4, CXCL9, 107 CXCL10, FAS, KITLG, C1QBP, NDUFA9, 85% 83% 81% 86% 81% 72% SLC25A11, ME2, CXCL11, IFT20, TLK1, RBM25, AK2, BRRN1, ATP5A1, CDC42BPA, RBBP4, AGPAT5, MARCH5, SEClOL1, PBK, HNRPD, BRIPI, TRMT5, ETNK1, STAT1 WARS, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, CXCL9, GTSE1, RABIF, 108 CXCL1O, FAS, PLK4, SLC25A1 1, NDUFA9, KPNB1, HNRPD, ME2, FUT4, CXCL11, GZMB, 81% 83% 85% 69% 73% 79% IFT20, RBBP4, RBM25, CAMSAP1L1, hCAP-D3, SFRS2, DDAH2, AGPAT5, MARCH5, PBK, BRIP1, TRMT5, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, DCK, CDC40, RABIF, CXCL10, FAS, 109 , WHSC1, C1R5, A2, E12, 77% 79% 88% 79% 77% 72% CXCL1 1, TLK1, RBM25, ATP5A1, CDC42BPA, FLJ10534, MARCH5, DKFZp762E1312, SEC1OL1, PBK, PSAT1, KLHL24, STATIC HNRPD, WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHIFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, ARF6, MAD2L1, CDC40, CXCL9, 110 GTSEl, CXCL1O, FAS, PLK4, CHEKI, HNRPA3P1, C1QBP, NDUFA9, SLC25A11, 73% 79% 85% 83% 88% 83% WHSC1, CA2, ME2, CXCL11, IFT20, TLK1, RBM25, ATP5A1, SOCS6, AGPAT5, SEC1OL1, PBK, TRMT5, KLHL24 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, 111 TYMS, TES, CTSS, MAD2L1, CXCL9, CXCL10, 81% 90% 88% 83% 77% 76% FAS, PLK4, CHEKI, SLC25A1 1, C1QBP, WHSC1, C17orf25, CA2, ME2, CXCL11, GZMB, 85 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN TLK1, SLC4A4, RBM25, AK2, hCAP-D3, FLJ10534, SEC10L1, FLJ13220, PBK, BRIPI, KLHL24, STAT1 WARS, SFRS2, EPASI, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, MAD2L1, CXCL9, CXCL1O, TRIM25, 112 NDUFA9, KPNB1, SLC25A11, WHSC1, C17or125, CA2, HNRPD, ME2, CXCL 11, GZMB, 96% 90% 81% 76% 77% 76% TLK1, RBM25, AK2, CAMSAP1LI, BRRN1, CDC42BPA, DDAH2, FAS, MARCH, SEC1OL1, PBK, PSATI, BRIP1, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, ARF6, 113 CDC40, CXCL9, CXCL10, FAS, PLK4, KITLG 65% 76% 88% 76% 85% 83% C1QBP, NDUFA9, SLC25A 11, WHSC1, C17orf25, CA2, ME2, FUT4, TLK1, CXCL 11, SLC4A4, RBM25, AK2, ATP5A1, AGPAT5, FLJ10534, MARCH5, SEC1OL1, PBK, PSAT1 HNRPD, WARS, SFRS2, STAT1, MTIFD2, PSME2, MCM6, TK1, GMFB, TYMS, USP4, LMAN1, ARF6, CXCL10, FAS, PLK4, SLC25A1 1, 114 C1QBP, NDUFA9, WHSC1, C17orf25, CA2, ME2, 81% 76% 81% 79% 85% 62% GZMB, RBBP4, CXCL11, RBM25, AK2, BRRN1, ATP5A1, CDC42BPA, DDAH2, BAZ1A, AGPAT5, MARCH5, SEC1OL1, PBK, BRIP1 HNRPD, WARS, EPASI, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMWB, DLGAP4, TYMS, TES, LMAN1, DCK, ARF6, 115 CXCL9, IRF8, GTSE1, CXCL1O, KITLG, NDUFA9, KPNB1, C17orf25, CA2, ME2, FUT4, 81% 86% 81% 76% 81% 79% CXCL1 1, GZMB, IFT20, TLK1, SLC4A4, RBM25, AK2, BRRN1, DDAH2, FAS, FLJ13220, PBK, PSATI, BRIPI WARS, SFRS2, EPASI, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TKI, GMFB, DLGAP4, TYMS, CTSS, ARF6, CDC40, CXCL9, CXCL10, 116 FAS, HNRPA3P1, TRIM25, SLC25A11, NDUFA9, 81% 79% 73% 90% 73% 69% WHSC1, HNRPD, ME2, FUT4, CXCL1 1, SLC4A4, RBM25, CAMSAP1L1, hCAP-D3, DDAH2, MARCH5, FLJ13220, PBK, PSATI, TRMT5, ETNK1, STAT1 WARS, SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, ARF6, MAD2L1, CDC40, 117 SLC4A4, CXCL9, CXCL1O, FAS, PLK4, HNRPA3P1, TRIM25, NDUFA9, SLC25A11, 92% 90% 88% 79% 81% 72% WHSC1, C17orf25, CA2, ME2, CXCL1 1, GZMB, IFT20, TLK1, RBM25, ATP5A1, RBBP4, AGPAT5, PSAT1, HNRPD, KLHL24, STATIC WARS, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, DLGAP4, TYMS, DCK, ARF6, MAD2L1, CDC40, CXCL9, IRF8, GTSE1, RABIF, 118 CXCL1O, FAS, CHEK1, TRIM25, C1QBP, 77% 90% 88% 76% 73% 79% NDUFA9, KPNB1, SLC25A1 1, WHSC1, C17orf25, CA2, ME2, GZMB, IFT20, TLK1, CXCL1 1, RBM25, AK2, SFRS2, BAZ1A, 86 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN SEC1OL1, FLJ13220, PBK, PSATI, HNRPD, BRIP1, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, CXCL1O, PLK4, CHEK1, KITLG, C1QBP, 119 NDUFA9, KPNB1, SLC25A11, WHSC1, CA2, 77% 76% 92% 83% 92% 76% ME2, FUT4, CXCL1 1, RBM25, AK2, hCAP-D3, BRRN1, FAS, AGPAT5, FLJ10534, MARCH, SEClOL1, PBK, TRMT5, KLHL24, ETNK1, STAT1 WARS, SFRS2, EPAS1, EIF4E, SFPQ, MTHFD2, PSME2, GMFB, TYMS, USP4, CTSS, LMAN1, DCK, MAD2L1, CDC40, SLC4A4, CXCL9, 120 CXCL1, , 81% 86% 88% 83% 85% 72% NDUFA9, CA2, NM2, 1FT20, CXCL1 1, RBM25 8% 8% 8% 3 5 2 AK2, CAMSAP1L1, hCAP-D3, ATP5A1, CDC42BPA, BAZ1A, AGPAT5, SEC10L1, PBK, HNRPD, BRIPI, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, MAD2L1, CDC40, CXCL9, CXCL1O, 121 CHEKI, TRIM25, SLC25A11, WHSC1, CA2, ME2, CXCL11, IFT20, RBBP4, SLC4A4, RBM2 85% 90% 88% 90% 85% 76% AK2, NUP210, hCAP-D3, DDAH2, FAS, BAZIA, FLJ10534, FLJ13220, PBK, BRIP1, TRMT5, ETNK1, STATIC HNRPD, WARS, EPAS1, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, CDC40, CXCL9, CXCL10, FAS, 122 PLK4, KITLG, C1QBP, NDUFA9, SLC25A11. 69% 76% 77% 86% 69% 69% WHSC1, C17orf25, ME2, CXCL11, RBM25, hCAP-D3, BRRN1, ATP5A1, CDC42BPA, FLJ10534, MARCH5, SEC10L1, FLJ13220, PBK, BRIP1, TRMT5, KLHL24, ETNK1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, CDC40, CXCL9, IRF8, CXCL1O, FAS, PLK4, CHEKI, HNRPA3P1, 123 C1QBP,NDUFA9, SLC25A11, WHSC1, Cl7orf25, 73% 83% 85% 76% 81% 79% CA2, HNRPD, ME2, SLC4A4, CXCL1 1, RBM25, AK2, NUP210, AGPAT5, FLJ10534, MARCH, DKFZp762E1312, PSATI, BRIP1, TRMT5, STAT1 WARS, SFRS2, EPASI, PAICS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CDC40, CXCL9, CXCL1O, FAS, PLK4, 124 HNRPA3P1, KITLG, C1QBP, NDUFA9, WHSC1, 77% 76% 92% 76% 85% 72% CA2, HNRPD, ME2, FUT4, CXCL11, GZMB, SLC4A4, RBM25, AK2, BRRN1, ATP5A1, AGPAT5, MARCH5, SEClOL1, FLJ13220, PBK, TRMT5, KLHL24, ETNK1, STAT1 WARS, SFRS2, EPAS1, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, 125 USP4, TES, CTSS, MAD2L1, CXCL9, IRF8, 85% 86% 92% 86% 88% 83% GTSE1, CXCL1O, PLK4, CHEK1, TRIM25, NDUFA9, SLC25A11, C17orf25, CA2, HNRPD, 87 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN ME2, CXCL1 1, IFT20, TLK1, RBM25, BRRN1, FAS, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, BRIPI, KLHL24 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, ARF6, MAD2L1, 126 CXCL9, GTSEl, CXCL10, FAS, HNRPA3P1, 77% 83% 88% 86% 85% 72% NDUFA9, KPNB1, SLC25A1 1, CA2, ME2, CXCL11, TLK1, SLC4A4, RBM25, BRRN1, AGPAT5, MARCH5, DKFZp762E1312, SEC1OL1, PBK, BRI1, KLHL24, STATIC WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, CDC40, CXCL9, IRF8, CXCL1O, PLK4, CHEK1, TRIM25, C1QBP, NDUFA9, 127 SLC25A11, WHSC1, ME2, FUT4, CXCL11, 73% 83% 73% 90% 73% 86% TLK1, SLC4A4, RBM25, AK2, CAMSAP1L1, BRRN1, ATP5A1, SFRS2, FAS, SEC10LI, FLJ13220, PBK, PSATI, TRMT5, KLBL24, STAT1 HNRPD, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, ARF6, MAD2L1, CDC40, CXCL9, IRF8, CXCL1O, 128 FAS, CHEKI, SLC25A1 1, C1QBP, NDUFA9, 69% 83% 77% 83% 85% 76% WHSC1, CA2, ME2, CXCL1 1, TLK1, SLC4A4, RBM25, AK2, BRRN1, SOCS6, DDAH2, RBBP4, FLJ10534, MARCH5, FLJ13220, PBK, BRIP1, ETNKI, STATIC WARS, SFRS2, EPASI, STATIC, EI4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, DCK, CDC40, SLC4A4, 129 CXCL9, IRF8, CXCL10, FAS, C1QBP, NDUFA9, 73% 76% 92% 79% 85% 72% SLC25A11, WHSC1, C17or125, CA2, ME2, RBM25, NUP210, CDC42BPA, AGPAT5, SEC10L1, FLJ13220, HNRPD, BRIP1, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPASI, PAICS, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CTSS, CXCL9, IRF8, RABIF, 130 CXCL1O, FAS, PLK4, CHEKI, TRIM25, KITLG, 85% 83% 92% 72% 88% 76% SLC25A11, C1QBP, NDUFA9, CA2, ME2, CXCL11, RBBP4, SLC4A4, RBM25, AK2, AGPAT5, FLJ10534, FLJ13220, PBK, TRMT5, KLHL24, STAT1 WARS, SFRS2, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, CTSS, ARF6, CDC40, CXCL9, CXCL1O, FAS, HNRPA3P1, 131 TRIM25, KITLG, C1QBP, NDUFA9, KPNB1, 85% 83% 92% 86% 88% 79% SLC25A1 1, WHSC1, C17orf25, CA2, HNRPD, ME2, CXCL1 1, TLK1, SLC4A4, RBM25, AK2, hCAP-D3, BRRN1, SOCS6, DDAH2, RBBP4, AGPAT5, PBK, BRIPI, STATIC HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, 132 USP4, CTSS, LMANI, CDC40, CXCL9, CXCL1O, 77% 83% 88% 76% 85% 76% PLK4, HNRPA3P1, C1QBP, NDUFA9, SLC25A11, WHSC1, CA2, ME2, CXCL11, 88 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN GZMB, IFT20, SLC4A4, RBM25, AK2, ATP5A1, FAS, RBBP4, BAZ1A, MARCH5, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, TRMT5, KL1L24, STAT1 WARS, SFRS2, EPASI, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, 133 CXCL9, RABIF, CXCL10, FAS, PLK4, TRIM25, 77% 83% 88% 76% 85% 79% C1QBP, NDUFA9, SLC25A11, CA2, HNRPD, ME2, CXCL1 1, RBBP4, TLK1, RBM25, CDC42BPA, BAZIA, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIP1 WARS, SFRS2, EPAS1, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CTSS, LMAN1, ARF6, MAD2L1, CDC40, IRF8, GTSEI, CXCL10, KITLG, C1QBP, NDUFA9, 134 KPNB1, SLC25A11, WHSC1, ME2, CXCL11, 81% 86% 77% 93% 81% 79% RBBP4, TLK1, SLC4A4, RBM25, AK2, BRRN1, ATP5A1, CDC42BPA, DDAH2, FAS, MARCH, SEC10L1, FLJ13220, PBK, HNRPD, BRIP1, STATIC WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, DCK, CDC40, CXCL9, IRF8, 135 CXCL1O, FAS, PLK4, HNRPA3P1, C1QBP, NDUFA9, SLC25A11, WHSC1, CA2, ME2, FUT4, 77% 90% 88% 72% 85% 79% CXCL11, GZMB, SLC4A4, RBM25, AK2, ATP5A1, DDAH2, FLJ10534, PBK, HNRPD, BRIP1, ETNK1, STATIC WARS, SFRS2, STATIC, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, CXCL1O, FAS, 136 PLK4, HNRPA3P1, TRIM25, KITLG, SLC25AI1, 81% 79% 85% 79% 81% 69% C1QBP, NDUFA9, KPNB1, C17orf25, CA2, ME2, IFT20, RBBP4, CXCL11, RBM25, AK2, hCAP D3, ATP5A1, CDC42BPA, BAZIA, AGPAT5, PBK, BRIP1, KLHL24 WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, CXCL1O, FAS, KITLG, SLC25A1 1, C1QBP, 137 NDUFA9, KPNB1, WHSC1, CA2, ME2, IFT20, 85% 83% 81% 83% 73% 72% RBBP4, TLK1, CXCL11, SLC4A4, RBM25, AK2, CDC42BPA, MARCH, SEC10L1, FLJ13220, PBK, PSATI, HNRPD, BRIPI, TRMT5, KLHL24, STATIC WARS, SFRS2, EPASI, STATIC, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, ARF6, CXCL9, IRF8, CXCL10, CHEKI, ClQBP, 138 NDUFA9, SLC25A11, WHSC1, C17orf25, CA2, 73% 76% 85% 83% 81% 76% ME2, CXCL1 1, SLC4A4, RBM25, AK2, BRRNI, CDC42BPA, FAS, BAZIA, AGPAT5, FLJ10534, MARCH5, PBK, PSAT1, HNRPD, TRMT5, KLHL24 139 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, 85% 76% 85% 79% 77% 69% 89 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN TYMS, USP4, LMAN1, ARF6, CXCL9, CXCL10, PLK4, HNRPA3P1, TRIM25, KITLG, C1QBP, NDUFA9, KPNB1, SLC25A1 1, WHSC1, C17or125, HNRPD, ME2, FUT4, CXCL11, GZMB, RBM25, AK2, hCAP-D3, BRRN1, ATP5A1, FAS, AGPAT5, SEC10L1, FLJ13220, PSATI, TRMT5, ETNK1, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, SLC4A4, 140 CXCL9, CXCL1O, FAS, PLK4, CHEKI, TRIM25, 81% 90% 85% 79% 81% 72% C1QBP, NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, ME2, GZMB, RBM25, hCAP-D3, ATP5A1, AGPAT5, FLJ10534, PBK, PSAT1, BRIPI, TRMT5, STATIC WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, MAD2L1, CDC40, CXCL9, IRF8, CXCL1O, PLK4, HNRPA3P1, TRIM25, SLC25A1 1, NDUFA9, 141 WHSC1, Cl7orf25, ME2, FUT4, CXCL11, IFT20, 85% 83% 88% 83% 73% 79% SLC4A4, RBM25, AK2, CAMSAPILl, hCAP-D3, BRRN1, FAS, BAZ1A, AGPAT5, MARCH, SEC1OL1, FLJ13220, PSATI, HNRPD, BRIPI, TRMT5, STAT1 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, CDC40, SLC4A4, CXCL9, RABIF, CXCL1O, PLK4, NDUFA9, SLC25A1 1, WHSC1, 142 C17orf25, CA2, HNRPD, ME2, CXCL11, IFT20, 77% 83% 81% 83% 85% 79% RBM25, hCAP-D3, ATP5A1, SOCS6, CDC42BPA, FAS, RBBP4, BAZIA, DKFZp762E1312, SEC10L1, FLJ13220, PBK, PSATI, BRIP1, STATIC HNRPD, WARS, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, CDC40, CXCL9, IRF8, 143 CXCL10, PLK4, HNRPA3P1, KITLG, NDUFA9, 73% 72% 88% 79% 92% 76% KPNB1, SLC25A11, WHSC1, C17orf25, CA2, ME2, FUT4, CXCL 11, SLC4A4, RBM25, hCAP D3, DDAH2, FAS, RBBP4, AGPAT5, FLJ13220, PBK, BRIPI, TRMT5, KLHL24 WARS, SFRS2, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CDC40, CXCL9, 144 CXCL10, FAS, CHEKI, NDUFA9, KPNB1, WHSC1, CA2, ME2, GZMB, TLK1, RBM25, AK2, 7 79% 85% 79% 69% 76% CAMSAP1L1, hCAP-D3, FLJ10534, DKFZp762E1312, FLJ13220, HNRPD, STAT1 HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, DCK, 145 ARF6, CDC40, CXCL9, CXCL10, PLK4, TRIM25, 77% 79% 81% 86% 81% 83% C1QBP, KPNB1, SLC25A11, C17orf25, ME2, CXCL1 1, RBM25, hCAP-D3, DDAH2, FAS, MARCH5, STATIC WARS, STATIC, ElF4E, MTHFD2, PSME2, 146 DLGAP4, TYMS, ARF6, CXCL9, CXCL1O, KITLG, C1QBP, NDUFA9, SLC25A1, WIISC1, 81% 79% 88% 79% 85% 69% C17orf25, CA2, HNRPD, ME2, CXCL11, SLC4A4, _ 90 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN RBM25, hCAP-D3, SOCS6, CDC42BPA, FAS HNRPD, WARS, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, CDC40, 147 SLC4A4, CXCL9, CXCL1O, HNRPA3P1, NDUFA9, SLC25A1 1, CA2, ME2, TLK1, 88% 83% 92% 83% 85% 83% CXCL11, RBM25, ATP5A1, SFRS2, FAS, MARCH, SEC1OL1, PBK, TRMT5, STAT1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, TYMS, TES, LMAN1, ARF6, 148 CXCL9, CXCL10, FAS, HNRPA3PI, C1QBP, 73% 83% 88% 79% 85% 72% NDUFA9, SLC25A11, WHSC1, C17orf25, CA2, ME2, CXCL1 1, RBM25, SEC1OL1, HNRPD, KLHL24, ETNK1, STATIC WARS, EIF4E, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, MAD2L1, CDC40, CXCL10, HNRPA3P1, 149 NDUFA9, C17orf25, ME2, CXCL 11, SLC4A4, 77% 79% 85% 76% 88% 79% RBM25, AK2, CDC42BPA, DDAH2, FAS, RBBP4, BAZIA, AGPAT5, HNRPD, BRIP1, TRMT5, STAT1 WARS, SFRS2, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, CXCL9, IRF8, CXCL1O, FAS, PLK4, 150 CHEKI, TRIM25, KITLG, C1QBP, NDUFA9, 85% 83% 88% 86% 85% 79% SLC25A1 1, WHSC1, C17orf25, CA2, ME2, CXCL11, RBM25, FLJ10534, SEC1OL1, BRIPI, TRMT5, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CTSS, DCK, SLC4A4, 151 CXCL9, CXCL10, FAS, TRIM25, SLC25A11, 100% 97% 85% 86% 81% 72% C1QBP, NDUFA9, WHSC1, CA2, ME2, CXCL1 1, TLKI, RBM25, AK2, CDC42BPA, SEC10L1, FLJ13220, KLHL24, STATIC WARS, STATIC, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, DCK, MAD2L1, CDC40, CXCL9, IRF8, RABIF, CXCL1O, KITLG, 152 SLC25A11, NDUFA9, ME2, IFT20, TLK1, 85% 90% 81% 86% 65% 86% CXCL11, RBM25, AK2, FAS, AGPAT5, DKFZp762E1312, SEC1OL1, PSATI, HNRPD, TRMT5 WARS, EPAS1, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, 153 CXCL10, FAS, PLK4, CHEK1, ClQBP, SLC25A1 1, CA2, ME2, FUT4, IFT20, SLC4A4, 69% 86% 85% 86% 88% 79% RBM25, SFRS2, DDAH2, PBK, HNRPD, KLHL24, ETNK1, STAT1 HNRPD, WARS, STAT1, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, TES, MAD2L1, 154 CXCL9, IRF8, CXCL10, HNRPA3P1, C1QBP, 88% 83% 81% 83% 85% 72% NDUFA9, SLC25A11, ME2, FUT4, IFT20, hCAP D3, SOCS6, DDAH2, FAS, BAZIA, PBK, KLHL24 SFRS2, EPASI, EIF4E, PRDX3, PSME2, GMFB, TYMS, TES, LMAN1, SLC4A4, CXCL9, GTSE1, 155 CXCL10, C1QBP, NDUFA9, SLC25A11, CA2, 92% 83% 88% 83%, 77% 72% ME2, TLKI, RBM25, CDC42BPA, FAS, FLJ10534, MARCH, SEC1OL1, PBK, HNRPD, TRMT5, KLHL24, ETNK1, STATIC 91 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN WARS, STAT1, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, USP4, ARF6, CDC40, 156 CXCL9, IRF8, CXCL1O, FAS, PLK4, HNRPA3P1 KITLG, C1QBP, SLC25A1 1, ME2, FUT4, RBM25, 81% 83% 88% 79% 92% 79% DDAH2, RBBP4, AGPAT5, PBK, HNRPD, TRMT5, KLHL24 HNRPD, WARS, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, SLC4A4, 157 CXCL9, CXCL1O, FAS, HNRPA3P1, KITLG, 92% 86% 85% 69% 85% 69% SLC25A11, NDUFA9, CA2, ME2, IFT20, CXCL11, RBM25, BAZIA, AGPAT5, SEC1OL1, PBK, BRIP1, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, CXCL9, IRF8, 158 CXCL1O, PLK4, TRIM25, NDUFA9, WHSC1 C17orf25, CA2, ME2, CXCL11, RBBP4, TLK1, 69% 83% 92% 86% 88% 83% SLC4A4, RBM25, NUP210, FAS, AGPAT5, MARCH5, SEC10L1, HNRPD, STAT1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, 159 LMAN1, ARF6, CDC40, CXCL9, CXCL1O, CA2, 77% 76% 88% 79% 85% 66% HNRPD, ME2, CXCL1 1, SLC4A4, RBM25, CDC42BPA, FAS, BAZ1A, AGPAT5, FLJ13220, BRIP1, KLHL24, STATIC WARS, SFRS2, EPASI, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, LMAN1, ARF6, 160 CDC40, CXCL9, CXCL10, PLK4, NDUFA9, C17orf25, ME2, CXCL 11, SLC4A4, RBM25, FAS, 7 76% 77% 83% 77% 79% BAZIA, DKFZp762E1312, SEC1OL1, PBK, PSATI, HNRPD, STATIC EIF4E, PSME2, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, CXCL1O, FAS, TRIM25, KITLG, 161 NDUFA9, SLC25A11, WHSC1, C17orf25, HNRPD, ME2, CXCL11, IFT20, SLC4A4, RBM25, 92% 86% 85% 79% 88% 72% AK2, AGPAT5, MARCH5, SEC10L1, FLJ13220, KLHL24, STAT1 HNRPD, WARS, EPASI, EIF4E, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, 162 CDC40, CXCL1O, C1QBP, SLC25A11, C17orf25, 81% 79% 85% 72% 85% 76% ME2, CXCL11, SLC4A4, RBM25, CAMSAP1L1, CDC42BPA, FAS, MARCH5, SEC1OL1, FLJ13220, PBK, BRIPI, KLHL24, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, DLGAP4, TYMS, USP4, TES, DCK, CDC40, 163 CXCL1O, CHEK1, HNRPA3P1, NDUFA9, SLC25A11, WHSC1, C17orf25, CA2, ME2, 69% 86% 81% 83% 81% 79% RBBP4, SLC4A4, RBM25, FAS, SEClOL1, FLJ13220, BRIPI, TRMT5, STAT1 HNRPD, WARS, MTHFD2, TK1, GMFB, DLGAP4, TYMS, LMAN1, CDC40, GTSE1, 164 CXCLI0, CHEK1, NDUFA9, SLC25A11, WHSC1, 81% 83% 92% 79% 81% 83% C17orf25, CA2, ME2, FUT4, CXCL11, RBBP4, RBM25, AK2, BRRN1, FAS, AGPAT5, MARCH5, PBK, BRIP1, STAT1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, 165 PSME2, GMFB, DLGAP4, TYMS, USP4, DCK, 73% 83% 88% 79% 88% 76% CXCL9, CXCL1O, SLC25A11, C1QBP, NDUFA9, 92 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN KPNB1, WHSC1, ME2, CXCL11, SLC4A4, RBM25, CDC42BPA, FAS, AGPAT5, SEC10L1, HNRPD, BRIP1, TRMT5, STATIC WARS, EIF4E, MTHFD2, PSME2, GMFB, TYMS, TES, CDC40, IRF8, RABIF, CXCL1O, 166 PLK4, TRIM25, SLC25A11, WHSC1, C17orf25 76% 81% 83% 77% 76% CA2, ME2, TLK1, CXCL11, SLC4A4, RBM25, CDC42BPA, FAS, RBBP4, SEC1OL1, PBK, HNRPD, BRIPI, TRMT5, STATIC WARS, SFRS2, MTHFD2, PSME2, TK1, DLGAP4, TYMS, DCK, CDC40, CXCL9, CXCL1O, FAS, CHEKI, TRIM25, ClQBP, 167 SLC25A11, WHSC1, CA2, ME2, CXCL11, 88% 93% 85% 76% 88% 72% GZMB, IFT20, SLC4A4, RBM25, hCAP-D3, DDAH2, SEC1OL1, FLJ13220, PBK, KLHL24, STAT1 WARS, SFRS2, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, LMAN1, DCK, 168 CDC40, CXCL9, CXCL10, FAS, NDUFA9, WHSC1, HNRPD, ME2, SLC4A4, CXCL1 1, . 79% 81% 86% 85% 76% RBM25, NUP210, hCAP-D3, SEC10L1, PSATI, KLHL24, STAT1 SFRS2, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, ARF6, 169 CDC40, CXCL9, RABIF, CXCL10, KITLG, 73% 79% 85% 86% 88% 76% C1QBP, SLC25A11, C17orf25, CA2, ME2, CXCL1 1, SLC4A4, RBM25, CAMSAP1L1, FAS, HNRPD, BRIPI, STATIC WARS, SFRS2, PAICS, EIF4E, PSME2, GMFB, DLGAP4, TYMS, ARF6, MAD2L1, SLC4A4, 170 CXCL9, IRF8, CXCL1O, FAS, NDUFA9, WHSC1, 85% 83% 88% 83% 77% 76% CA2, ME2, CXCL1 1, TLK1, RBM25, AK2, AGPAT5, MARCH5, FLJ13220, TRMT5, STATIC SFRS2, EPASI, EIF4E, MTHFD2, GBP1, GMFB, CTSS, LMAN1, CDC40, CXCL9, CXCL10, FAS, 171 CHEKI, SLC25A11, C1QBP, C17orf25, CA2, 88% 86% 85% 86% 77% 79% ME2, IFT20, CXCL1 1, RBM25, BRRN1, ATP5A1, RBBP4, HNRPD, BRIP1, STATIC WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, CDC40, 172 SLC4A4, CXCL1O, KITLG, SLC25A11, C1QBP, 81% 79% 96% 86% 88% 83% NDUFA9, CA2, HNRPD, ME2, FUT4, CXCL1 1, RBM25, ATP5A1, FAS, RBBP4, BRIP1, TRMT5, STAT1 WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, TYMS, TES, LMAN1, DCK, CXCL9, 173 CXCL1O, KITLG, KPNB1, SLC25A11, ME2, CXCL1 1, IFT20, TLK1, RBM25, CDC42BPA, 77% 79% 77% 86% 73% 86% FAS, BAZIA, FLJ10534, MARCH5, SEC1OL1, HNRPD, BRIPI, TRMT5, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, TK1, GMFB, DLGAP4, TYMS, 174 LMAN1, CDC40, SLC4A4, CXCL9, IRF8, RABIF 85% 79% 88% 83% 85% 86% CXCL10, SLC25A11, NDUFA9, CA2, ME2, CXCL1 1, RBBP4, RBM25, NUP210, FAS, SEC1OL1, PBK, STAT1 175 HNRPD, WARS, EPAS1, PRDX3, MTHFD2, 85% 90% 88% 83% 85% 72% 93 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN PSME2, DLGAP4, TYMS, CDC40, IRF8, CXCL10, FAS, SLC25A11, C1QBP, CA2, ME2, GZMB, IFT20, SLC4A4, AK2, NUP210, RBBP4, AGPAT5, MARCH5, FLJ13220, STATIC HNRPD, WARS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CXCL9, CXCL10, FAS, 176 C1QBP, NDUFA9, SLC25A1 1, CA2, ME2, 81% 79% 88% 76% 88% 79% RBBP4, SLC4A4, CXCL1 1, RBM25, ATP5A1, DDAH2, BAZIA, PBK, BRIP1, STATIC HNRPD, WARS, SFRS2, EPAS1, STATIC, EIF4E, PRDX3, PSME2, DLGAP4, TYMS, TES, LMAN1, 177 CDC40, CXCL10, FAS, C1QBP, NDUFA9, SLC25A11, CA2, ME2, GZMB, IFT20, CXCL11, 96% 93% 92% 76% 88% 76% SLC4A4, RBM25, AK2, AGPAT5, DKFZp762E1312, SEC 1 OL1, BRIP 1, KLHL24 WARS, EIF4E, PRDX3, MTHFD2, TK1, GMFB, TYMS, CDC40, CXCL9, IRF8, CXCL10, FAS, 178 CHEKI, TRIM25, SLC25A1 1, NDUFA9, CA2, 85% 83% 88% 79% 88% 72% ME2, IFT20, RBM25, AK2, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, HNRPD, STAT1 WARS, EIF4E, PRDX3, MTHFD2, GBP1, GMFB, DLGAP4, TYMS, USP4, IRF8, CXCL10, FAS, 179 TRIM25, C1QBP, NDUFA9, SLC25A1 1, WHSC1, 85% 86% 88% 76% 81% 76% CA2, HNRPD, ME2, GZMB, TLK1, CXCL11, RBM25, DKFZp762E1312, PSAT1, BRIPI, TRMT5, KLHL24, STAT1 WARS, EPASI, STATIC, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, 180 LMAN1, CXCL9, IRF8, CXCL10, C1QBP, NDUFA9, SLC25A1 1, WHSC1, HNRPD, ME2, 92% 90% 88% 79% 73% 76% CXCL1 1, IFT20, TLK1, SLC4A4, CDC42BPA, SFRS2, FAS, PSATI WARS, EIF4E, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, FAS, PLK4, 181 C1QBP, CA2, HNRPD, ME2, CXCL11, RBM25, 77% 79% 81% 79% 85% 76% RBBP4, SEC1OL1, FLJ13220, PBK, BRIPI, TRMT5, KLHL24, ETNK1, STATIC WARS, SFRS2, EIF4E, MTHFD2, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, IRF8, 182 GTSE1, CXCL1O, HNRPA3P1, SLC25A11, 88% 83% 85% 83% 77% 86% NDUFA9, CA2, HNRPD, ME2, RBBP4, SLC4A4, RBM25, BRRN1, FAS, BAZ1A, BRIP1, STATIC HNRPD, WARS, EPAS1, EIF4E, MTHFD2, TK1, GMFB, DLGAP4, LMAN1, ARF6, MAD2L1, 183 CDC40, CXCL9, CXCL1O, HNRPA3P1, TRIM25, 88% 90% 81% 86% 81% 79% C1QBP, NDUFA9, SLC25A1 1, WHSC1, C17orf25, ME2, CXCL1 1, SLC4A4, RBM25, DDAH2, FAS, ETNK1, STAT1 HNRPD, WARS, PAICS, MTHFD2, PSME2, DLGAP4, TYMS, USP4, CXCL9, CXCL10, 184 KITLG, C1QBP, NDUFA9, SLC25A11, WHSC1, 73% 83% 77% 69% 69% 69% ME2, CXCL1 1, SLC4A4, RBM25, NUP2 10, ATP5A1, CDC42BPA, FAS, MARCH5, DKFZp762E1312, SEC1OL1, PBK, BRIP1, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, 185 MTHFD2, PSME2, GMFB, DLGAP4, DCK, 81% 86% 81% 86% 73% 83% MAD2L1, CXCL9, CXCL10, FAS, PLK4, 94 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN TRIM25, KITLG, SLC25A1 1, WHSC1, ME2, FUT4, CXCL11, SLC4A4, RBM25, NUP210, DDAH2, RBBP4, BAZ1A, AGPAT5, FLJ10534, MARCH5, DKFZp762E1312, SEC1OL1, PSAT1, BRIPI, TRMT5, STAT1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, TYMS, LMAN1, ARF6, CDC40, CXCL9, IRF8, RABIF, 16 CXCL1O, FAS, PLK4, C1QBP, NDUFA9,85 79 8% 7% 73 76 186 SLC25A1, WHSC1, Cl7orf25, M2, FUT4, 85% 79% 85% 79% 73% 76% CXCL1 1, IFT20, SLC4A4, RBM25, AK2, SOCS6, MARCH, SEC1OL1, FLJ13220, PBK, HNRPD, BRIPI, TRMT5, STATIC HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, ARF6, CDC40, SLC4A4, CXCL9, 187 RABIF, CXCL10, FAS, PLK4, C1QBP, NDUFA9, 77% 83% 85% 79% 81% 79% SLC25A11, WHSC1, CA2, ME2, CXCL11, TLK1, RBM25, ATP5A1, CDC42BPA, RBBP4, AGPAT5, SEC10L1, FLJ13220, PSAT1, BRIP1, STAT1 HNRPD, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, ARF6, MAD2L1, 188 CDC40, CXCL9, CXCL1O, FAS, PLK4, NDUFA9, 77% 86% 85% 83% 85% 76% WHSC1, C17orf25, CA2, ME2, CXCL11, GZMB, TLK1, SLC4A4, RBM25, AK2, NUP210, hCAP D3, DDAH2, RBBP4, PBK, BRIPI, STATIC WARS, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, USP4, CTSS, ARF6, CDC40, SLC4A4, CXCL9, CXCL 10, FAS, SLC25A11, 189 ClQBP, NDUFA9, WHSC1, C17orf25, CA2, ME2, 77% 79% 96% 79% 85% 72% FUT4, CXCL1 1, GZMB, TLK1, RBM25, NUP210, CDC42BPA, AGPATS, MARCH5, SEC1OL1, PBK, HNRPD, TRMT5, KLHL24, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTIFD2, PSME2, GBP1, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, IRF8, CXCL1O, 190 FAS, TRIM25, SLC25A1 1, NDUFA9, WHSCI, 92% 79% 85% 83% 69% 79% CA2, ME2, TLK1, CXCL11, SLC4A4, RBM25, AK2, hCAP-D3, DDAH2, FLJ10534, SEClOL1, BRIPI, STATIC WARS, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, TES, LMAN1, CDC40, CXCL9, IRF8, RABIF, CXCL10, FAS, SLC25A11, 191 C1QBP, NDUFA9, WHSC1, CA2, ME2, CXCL11, 77% 83% 85% 76% 85% 79% SLC4A4, RBM25, AK2, hCAP-D3, SOCS6, CDC42BPA, FLJ10534, DKFZp762E1312, SEC10L1, FLJ13220, PBK, HNRPD, TRMT5, STATIC WARS, SFRS2, STATIC, EI4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, CTSS, CDC40, CXCL9, 192 CXCL1O, PLK4, KITLG, SLC25A11, C1QBP NDUFA9, C17orf25, CA2, ME2, CXCL11, IFT20, 73% 86% 85% 83% 85% 83% RBM25, hCAP-D3, ATP5A1, FAS, FLJ10534, MARCH, SEC10L1, PBK, HNRPD, BRIPI, TRMT5 95 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN HNRPD, WARS, EPASI, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, MAD2L1, CXCL9, CXCL10, FAS, 193 PLK4, HNRPA3P1, C1QBP, NDUFA9, 77% 76% 85% 83% 81% 72% SLC25A11, WHSC1, C17orf25, CA2, ME2, SLC4A4, RBM25, hCAP-D3, SOCS6, BAZ1A, FLJ10534, SEC10L1, FLJ13220, PBK, BRIP1 SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, CDC40, CXCL9, CXCL10, FAS, 194 TRIM25, C1QBP, NDUFA9, SLC25Al1, WHSC1, 77% 83% 85% 83% 81% 76% CA2, ME2, CXCL 11, IFT20, RBBP4, SLC4A4, RBM25, AK2, hCAP-D3, BRRN1, CDC42BPA, MARCH, FLJ13220, HNRPD, STATIC WARS, SFRS2, EPAS1, EIF4E, SFPQ, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, DCK, ARF6, CDC40, CXCL10, FAS, CHEKI, 195 HNRPA3P1, SLC25A11, NDUFA9, CA2, HNRPD, 81% 86% 88% 76% 85% 79% ME2, GZMB, RBBP4, TLK1, SLC4A4, CXCL1 1, RBM25, ATP5A1, AGPAT5, FLJ10534, FLJ13220, ETNK1, STATIC WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, ARF6, CDC40, SLC4A4, CXCL9, GTSE1, 196 RABIF, CXCL1O, FAS, HNRPA3P1, KITLG, 88% 83% 88% 79% 88% 72% NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, HNRPD, ME2, CXCL1 1, RBBP4, RBM25, AK2, CDC42BPA, MARCH, TRMT5, KLHL24 WARS, SFRS2, EPASI, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, RABIF, CXCL1O, FAS, 197 PLK4, KITLG, C1QBP, NDUFA9, SLC25A1 1, 77% 79% 85% 79% 88% 79% WHSC1, CA2, HNRPD, ME2, FUT4, CXCL1 1, RBM25, CDC42BPA, MARCH5, DKFZp762E1312, SEC1OL1, PBK WARS, SFRS2, EPASI, EIF4E, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CDC40, RABIF, CXCL1O, PLK4, KITLG, C1QBP, 198 NDUFA9, SLC25A11, WHSC1, C17orf25, ME2, 85% 90% 77% 83% 77% 66% CXCL1 1, IFT20, RBM25, CAMSAP1L1, BRRN1, FAS, AGPAT5, PSATI, HNRPD, TRMT5, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, CXCL1O, FAS, 199 KITLG, C1QBP, NDUFA9, KPNB1, SLC25A1 1, 92% 90% 96% 76% 85% 76% CA2, ME2, GZMB, RBBP4, TLK1, CXCL11, RBM25, AK2, SOCS6, AGPAT5, SEC1OL1, PBK, STAT1 SFRS2, PAICS, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, DCK, ARF6, MAD2L1, CDC40, CXCL9, GTSE1, RABIF, CXCL1O, FAS, C1QBP, 200 NDUFA9, SLC25AI1, C17ort25, CA2, ME2, 81% 86% 88% 79% 73% 72% GZMB, IFT20, CXCL1 1, RBM25, AK2, hCAP-D3, BRRN1, AGPAT5, DKFZp762E1312, PBK, PSATI, HNRPD, TRMT5, ETNK1, STATIC 201 HNRPD, WARS, SFRS2, STAT1, EIF4E, 88% 93% 88% 76% 85% 66% 96 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN MTHFD2, PSME2, DLGAP4, TYMS, CXCL9, GTSE1, CXCL1O, FAS, CHEKI, HNRPA3P1, TRIM25, KITLG, NDUFA9, SLC25A11, WHSCI, CA2, ME2, GZMB, IFT20, SLC4A4, CXCL11, RBM25, CAMSAP1L1, hCAP-D3, BRRN1, AGPAT5, MARCH, DKFZp762E1312, SEC1OLl, PBK, BRIP WARS, SFRS2, STATIC, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, CTSS, ARF6, CDC40, CXCL9, CXCL1O, FAS, 202 HNRPA3P1, SLC25A11, CA2, HNRPD, ME2, 85% 86% 92% 76% 73% 72% FUT4, RBBP4, TLK1, CXCL1 1, SLC4A4, RBM25, AK2, CDC42BPA, AGPAT5, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, KLHL24, ETNK1 WARS, SFRS2, STAT1, MTHFD2, PSME2, GMFB, DLGAP4, SLC4A4, CXCL9, CXCL10, FAS, CHEKI, TRIM25, KITLG, SLC25A1 1, 203 C1QBP, NDUFA9, KPNB1, WHSCI, ME2, CXCL1 1, IFT20, RBM25, NUP210, CAMSAP1L1, 92% 86% 85% 76% 69% 69% BRRNI1, CDC42BPA, DDAH2, AGPAT5, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, HNRPD, TRMT5, KLHL24 WARS, SFRS2, EPASI, EIF4E, PSME2, MCM6, GMFB, DLGAP4, TYMS, DCK, ARF6, SLC4A4, CXCL9, IRF8, CXCL10, FAS, KITLG, NDUFA9, 204 SLC25A11, WHSCI, CA2, HNRPD, ME2, FUT4, 85% 83% 85% 76% 81% 72% GZMB, IFT20, RBBP4, CXCL1 1, RBM25, AK2, AGPAT5, MARCH, SEC10L1, FLJ13220, PBK, BRIP1, ETNK1, STAT1 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, MAD2L1, CDC40, SLC4A4, CXCL9, 205 GTSE1, RABIF, CXCL1O, FAS, PLK4, TRIM25, 96% 86% 81% 79% 85% 72% C1QBP, NDUFA9, SLC25A1 1, CA2, HNRPD, ME2, CXCL1 1, IFT20, RBM25, BRRN1, CDC42BPA, DDAIH2, PSATI, KLHL24, STAT1 WARS, PAICS, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, ARF6, SLC4A4, CXCL9, CXCL10, FAS, PLK4, TRIM25, 206 SLC25A11, C1QBP, NDUFA9, KPNB1, WHSC1, 81% 83% 88% 90% 77% 79% C17orf25, HNRPD, ME2, CXCL1 1, IFT20, TLK1, RBM25, AK2, AGPAT5, SEC1OL1, FLJ13220, BRIP1, TRMT5, KLHL24, STAT1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, ARF6, CDC40, CXCL9, CXCL10, FAS, 207 NDUFA9, KIPNB, SC C170r, CBP, 85% 90% 96% 79% 85% 79% HNRPD, ME2, FUT4, CXCL1 1, GZMB, IFT20, SLC4A4, RBM25, AK2, SEC10L1, PBK, BRIPI, STAT1 HNRPD, WARS, EPASI, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, 208 TYMS, TES, CDC40, CXCL9, IRF8, GTSE1, CXCL1O, FAS, C1QBP, NDUFA9, C17orf25, 77% 79% 81% 83% 73% 72% ME2, SLC4A4, CXCL1 1, RBM25, NUP210, FLJ10534, MARCH5, DKFZp762E1312, 97 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN FLJ13220, PBK, BRIPI, TRMT5, ETNK1 WARS, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, USP4, LMAN1, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, GTSEl, RABIF, 209 CXCL1O, FAS, TRIM25, C1QBP, NDUFA9, 85% 86% 88% 79% 85% 76% SLC25AI 1, C17orf25, CA2, ME2, CXCL1 1, GZMB, IFT20, TLK1, RBM25, AK2, SOCS6, RBBP4, AGPAT5, MARCH5, SEC1OL1, PBK, HNRPD, STATIC HNRPD, WARS, SFRS2, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, DLGAP4, TYMS, ARF6, MAD2L1, CDC40, CXCL9, RABIF, 210 CXCL1O, PLK4, CHEKI, TRIM25, C1QBP, 77% 79% 85% 86% 81% 79% NDUFA9, WHSC1, C17orf25, CA2, ME2, CXCL11, TLK1, BRRN1, SOCS6, FAS, AGPAT5, MARCH5, FLJ13220, PBK, TRMT5, KLHL24 WARS, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, MAD2L1, CDC40, RABIF, CXCL10, FAS, 211 LNRPA3P1, SLC25A 11, NDUFA9, C17orf25 ME2, CXCL11, SLC4A4, RBM25, AK2, hCAP- 77 79% 85% 76% 81% 72% D3, SOCS6, DDAH2, RBBP4, AGPAT5, DKFZp762E1312, SEC10L1, PBK, PSATI, HNRPD, BRIP1, ETNK1, STATIC HNRPD, WARS, EPAS1, STATIC, EIF4E, MTHFD2, GBP1, TK1, GMFB, DLGAP4, TYMS, LMAN1, DCK, CDC40, CXCL9, IRF8, CXCL10, 212 FAS, PLK4, HNRPA3P1, SLC25A11, NDUFA9, 81% 83% 85% 76% 77% 79% KPNB1, WHSC1, CA2, ME2, CXCL11, GZMB, RBBP4, SLC4A4, RBM25, NUP210, DDAH2, PBK, KLHL24, ETNK1 HNRPD, WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, DCK, ARF6, CDC40, CXCL9, IRF8, CXCL10, FAS, TRIM25, 213 SLC25A11, C1QBP, C17orf25, CA2, ME2, 100% 90% 92% 72% 85% 79% CXCL1 1, GZMB, IFT20, TLK1, RBM25, AK2, CDC42BPA, SEC1OL1, FLJ13220, PBK, BRIP1, KLHL24, ETNK1 WARS, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CDC40, CXCL9, IRF8, GTSE1, CXCL1O, FAS, PLK4, TRIM25, C1QBP, 214 SLC25A11, C17orf25, CA2, HNRPD, ME2, 81% 79% 85% 79% 85% 72% CXCL1 1, IFT20, AK2, BRRN1, SOCS6, CDC42BPA, SFRS2, RBBP4, MARCH5, SEC1OL1, FLJ13220, PSAT1, BRIPI, TRMT5, KLHL24, STAT1 HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, MAD2L1, CDC40, CXCL9, IRF8, GTSE1, 215 CXCL1O, SLC25A1 1, NDUFA9, WHSC1, CA2 85% 86% 88% 72% 81% 72% ME2, CXCL1 1, IFT20, RBM25, AK2, BRRN1, CDC42BPA, FAS, RBBP4, BAZ1A, AGPAT5, SEC1OL1, FLJ13220, PBK, BRIP1, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, 216 MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, 73% 83% 88% 79% 85% 72% CTSS, LMAN1, CDC40, CXCL9, IRF8, CXCL1O, 98 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN FAS, PLK4, HNRPA3P1, KITLG, CIQBP, NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, ME2, CXCL11, RBM25, AK2, hCAP-D3, BAZIA, AGPAT5, DKFZp762E1312, PBK, BRIP1 WARS, EIF4E, MTHFD2, PSME2, MCM6, DLGAP4, TYMS, USP4, TES, DCK, ARF6, MAD2L1, CDC40, CXCL9, IRF8, CXCL1O, PLK4, 217 HNRPA3P1, TRIM25, SLC25A11, ClQBP, 85% 86% 81% 79% 77% 76% WHSCI, CA2, ME2, CXCL1 1, GZMB, IFT20, TLK1, SLC4A4, RBM25, SOCS6, DDAH2, FAS, FLJ13220, PBK, KLHL24, ETNK1, STAT1 WARS, SFRS2, EPASI, STATIC, PAICS, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, SLC4A4, CXCL9, 218 IRF8, CXCL1O, FAS, PLK4, CHEK1, HNRPA3P1, 81% 83% 85% 83% 88% 76% TRlI25, C1QBP, NDUFA9, CA2, ME2, FUT4, CXCL1 1, RBM25, AK2, ATP5A1, AGPAT5, SEC1OL1, FLJ13220, HNRPD, KLHL24 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, CDC40, CXCL9, CXCL 10, FAS, PLK4, 219 HNRPA3P1, SLC25A11, NDUFA9, WHSC1, C17orf25, CA2, ME2, CXCL11, IFT20, RBM25, 81% 79% 85% 79% 88% 76% hCAP-D3, ATP5A1, RBBP4, AGPAT5, FLJ10534, MARCH5, SEC10L1, HNRPD, BRIP1, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPAS1, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, TYMS, USP4, TES, LMAN1, CDC40, CXCL9, CXCL1O, FAS, C1QBP, 220 SLC25A1 1, WHSC1, CA2, ME2, FUT4, TLK1, 73% 79% 85% 79% 85% 83% CXCL1 1, SLC4A4, RBM25, hCAP-D3, DDAH2, BAZIA, FLJ10534, MARCH5, FLJ13220, PBK, PSAT1, BRIPI, TRMT5, STATIC HNRPD, EPASI, STATIC, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, CXCL9, CXCL10, FAS, CHEKI, 221 HNRPA3P1, C1QBP, NDUFA9, KPNB1, 81% 83% 88% 83% 85% 86% SLC25A11, WHSC1, CA2, ME2, CXCL11, TLK1, RBM25, ATP5A1, DDAH2, RBBP4, SEC1OLI, PBK, BRIPI, ETNK1 WARS, SFRS2, EIF4E, MTHFD2, PSME2, DLGAP4, TYMS, ARF6, CXCL9, IRF8, GTSE1, RABIF, CXCL10, FAS, PLK4, KITLG, 222 SLC25A11, C1QBP, NDUFA9, ME2, CXCL11, 88% 86% 92% 72% 81% 72% GZMB, IFT20, RBBP4, SLC4A4, RBM25, AK2, BAZIA, AGPAT5, MARCH5, FLJ13220, HNRPD, BRIP1, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, STATIC, EIF4E, MTHJFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, ARF6, CXCL9, GTSE1, CXCL1O, FAS, 223 PLK4, HNRPA3P1, TRIM25, KITLG, C1QBP, 85% 83% 88% 76% 81% 83% SLC25A11, WHSC1, C17orf25, CA2, ME2, CXCL11, TLK1, RBM25, ATP5A1, AGPAT5, FLJ10534, MARCH5, FLJ13220, PBK, BRIPI, TRMT5 224 HNRPD, WARS, SFRS2, EIF4E, PRDX3, 24 MTHFD2, PSME2, GMFB, DLGAP4, TYMS, 85% 79% 92% 76% 85% 72% 99 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN USP4, TES, CDC40, SLC4A4, CXCL9, CXCL1O, FAS, TRIM25, KITLG, C1QBP, NDUFA9, C17orf25, CA2, ME2, GZMB, TLK1, CXCL1 1, RBM25, CAMSAP1L1, CDC42BPA, DDAH2, BAZIA, AGPAT5, SEClOL1, PBK, KLHL24, ETNK1, STAT1 WARS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, ARF6, CDC40, CXCL9, IRF8, CXCL1O, FAS, PLK4, 225 CHEKI, TRIM25, C1QBP, NDUFA9, SLC25A11, 81% 79% 88% 76% 88% 79% WHSC1, CA2, HNRPD, ME2, CXCL1 1, GZMB, IFT20, RBBP4, SLC4A4, RBM25, ATP5A1, PBK, BRIPI, TRMT5, STATIC HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, DCK, CXCL9, CXCL1O, FAS, HNRPA3P1, TRIM25, 226 C1QBP, NDUFA9, SLC25A1 1, WHSCI, ME2 SLC4A4, CXCL11, RBM25, BRRN1, BAZ1A, 79% 77% 86% 73% 69% AGPAT5, FLJ10534, MARCH, SEC1OL1, FLJ13220, PBK, PSAT1, BRIP1, TRMT5, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPASI, PRDX3, PSME2, GBP1, TK1, DLGAP4, TYMS, DCK, ARF6, CDC40, CXCL9, GTSE1, RABIF, CXCL1O, 227 FAS, TRIM25, ClQBP, NDUFA9, SLC25A1 1, 81% 90% 92% 76% 88% 69% C17orf25, CA2, ME2, CXCL 11, GZMB, IFT20, RBBP4, RBM25, AGPAT5, MARCH, SEC10L1, FLJ13220, PBK, BRIPI, STATIC WARS, SFRS2, EPASI, STATIC, EIF4E, MTHFD2, GMFB, DLGAP4, TYMS, TES, CTSS, CXCL9, CXCL10, FAS, PLK4, CHEKI, TRIM25, 228 SLC25A11, NDUFA9, WHSC1, C17orf25, CA2, 77% 83% 88% 76% 88% 76% ME2, FUT4, CXCL1 1, SLC4A4, RBM25, AK2, BRRN1, CDC42BPA, DDAH2, AGPAT5, MARCH, PBK, HNRPD, KLHL24 HNRPD, WARS, SFRS2, EPAS1, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, CXCL9, IRF8, RABIF, FAS, PLK4, TRIM25, 229 SLC25A11, C1QBP, WHSCI, C17orf25, CA2, 85% 86% 85% 72% 85% 76% ME2, FUT4, CXCL1 1, GZMB, IFT20, RBM25, SOCS6, DDAH2, MARCH5, PBK, PSATI, BRIP1, TRMT5, STATIC WARS, SFRS2, STATIC, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, ARF6, CDC40, CXCL9, CXCL1O, FAS, HNRPA3P1, 230 C1QBP, SLC25A11, WHSC1, ME2, CXCL11, 73% 83% 81% 76% 69% 66% RBBP4, SLC4A4, RBM25, AK2, hCAP-D3, CDC42BPA, FLJ10534, SEC1OL1, FLJ13220, PBK, PSAT1, HNRPD, BRIP1, TRMT5, KLHL24 SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, CXCL9, IRF8, CXCL1O, CHEK1, 231 HNRPA3P1, KITLG, SLC25A11, C1QBP, 73% 76% 92% 72% 77% 76% NDUFA9, WHSC1, C17orf25, ME2, FUT4, CXCL11, GZMB, RBM25, CDC42BPA, FAS, RBBP4, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, HNRPD, TRMT5, STAT1 100 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN HNRPD, WARS, SFRS2, PAICS, EIF4E, MTHFD2, PSME2, MCM6, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CDC40, CXCL9, IRF8, RABIF, CXCL1O, CHEKI, C1QBP, 232 NDUFA9, SLC25A11, WHSC1, CA2, ME2, FUT4, 73% 79% 88% 86% 81% 83% CXCL11, IFT20, TLK1, SLC4A4, RBM25, NUP210, CAMSAP1L1, BRRN1, FAS, RBBP4, BAZ1A, FLJ10534, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, KLHL24, STATIC WARS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, DCK, ARF6, MAD2L1, CDC40, SLC4A4, CXCL9, GTSE1, CXCL1O, FAS, KITLG, NDUFA9, 233 SLC25Al1, WHSC1, C17orf25, CA2, HNRPD, 77% 79% 92% 76% 88% 76% ME2, FUT4, CXCL1 1, GZMB, IFT20, TLK1, RBM25, AK2, CAMSAP1L1, DDAH2, RBBP4, BAZIA, AGPAT5, SEC1OL1, PBK, BRIP1, KLHL24, ETNK1, STATIC WARS, SFRS2, EPASI, STATIC, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, ARF6, CDC40, CXCL9, IRF8, 234 RABIF, CXCL10, FAS, SLC25A11, NDUFA9 C17orf25, CA2, ME2, CXCL11, GZMB, IFT20, 85% 90% 92% 79% 77% 83% RBBP4, TLK1, SLC4A4, RBM25, NUP210, BRRN1, ATP5A1, AGPAT5, MARCH5, SEC10L1, PBK, PSATI, HNRPD, BRIPI, TRMT5 WARS, SFRS2, EPASI, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, ARF6, MAD2L1, CDC40, CXCL9, CXCLIO, PLK4, CHEK1, TRIM25, 235 KITLG, SLC25A11, C1QBP, KPNB1, WHSC1, 81% 90% 92% 76% 85% 69% C17orf25, CA2, HNRPD, ME2, GZMB, CXCL11, RBM25, BRRN1, ATP5A1, CDC42BPA, DDAH2, FAS, BAZIA, AGPAT5, FLJ10534, MARCH, SEC1 OL1, PBK, TRMT5, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, DCK, ARF6, MAD2L1, CDC40, CXCL9, RABIF, CXCL10, CHEKI, 236 HNRPA3P1, TRIM25, KITLG, C1QBP, NDUFA9, 81% 83% 88% 72% 81% 76% KPNB1, SLC25A11, WHSC1, CA2, ME2, GZMB, SLC4A4, CXCL11, RBM25, AK2, ATP5AI, DDAH2, FAS, BAZ1A, DKFZp762E1312, SEClOL1, FLJ13220, BRIPI, TRMT5, ETNK1, STAT1 WARS, SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, ARF6, MAD2L1, SLC4A4, CXCL9, GTSE1, CXCL1O, FAS, HNRPA3P1, 237 KITLG, SLC25A11, ClQBP, NDUFA9, KPNB1, 77% 83% 92% 83% 81% 76% C17orf25, CA2, HNRPD, ME2, CXCL1 1, GZMB, IFT20, RBBP4, RBM25, AK2, ATP5A1, BAZIA, AGPAT5, SEC10L1, FLJ13220, PBK, BRIP1, ETNK1, STATIC HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, 238 MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES CTSS, LMAN1, SLC4A4, CXCL9, IRF8, GTSE1, 85% 86% 88% 86% 85% 79% CXCL10, CHEKI, TRIM25, KITLG, SLC25A11, 101 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN C1QBP, NDUFA9, KPNB1, WHSC1, C17orf25, CA2, ME2, FUT4, TLK1, CXCL11, RBM25, BRRN1, DDAH2, FAS, RBBP4, AGPAT5, FLJ10534, MARCH, SEC1OL1, FLJ13220, PBK, TRMT5, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, IRF8, GTSE1, RABIF, CXCL1O, FAS, CHEKI, SLC25A1 1, 239 ClQBP, NDUFA9, WHSCI, Cl7orf25, CA2, ME2, 69% 79% 88% 83% 81% 76% IFT20, CXCL11, SLC4A4, RBM25, AK2, hCAP D3, ATP5A1, SOCS6, DDAH2, FLJ10534, MARCH5, SEC1OL1, PBK, PSAT1, BRIPI, STAT1 WARS, SFRS2, EPAS1, STATIC, EIF4E, PRDX3, MTHIFD2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, ARF6, MAD2L1, CXCL9, IRF8, RABIF, CXCL1O, FAS, HNRPA3P1, TRIM25, KITLG, 240 C1QBP,NDUFA9,SLC25A11,WHSC1,C17orf25, 81% 83% 96% 69% 81% 76% HNRPD, ME2, GZMB, SLC4A4, CXCL11, RBM25, AK2, CAMSAP1L1, hCAP-D3, BRRN1, CDC42BPA, RBBP4, BAZIA, FLJ10534, SEC10L1, BRIP1, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, MAD2L1, CDC40, CXCL9, RABIF, CXCL10, FAS, PLK4, TRIM25, 241 SLC25A11, NDUFA9, KPNB1, WHSCI, CA2, 73% 79% 88% 83% 92% 79% ME2, CXCL1 1, TLK1, SLC4A4, RBM25, hCAP D3, BRRN1, SOCS6, CDC42BPA, DDAH2, RBBP4, BAZIA, AGPAT5, DKFZp762E1312, SEC10L1, PBK, BRIP, KLHL24, ETNK1, STATIC WARS, STATIC, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, DCK, ARF6, MAD2L1, CDC40, CXCL9, RABIF, CXCL10, FAS, PLK4, TRIM25, KITLG, 242 SLC25A11,C1QBP,NDUFA9,KPNB1,Cl7orf25, 81% 83% 85% 79% 81% 69% CA2, ME2, CXCL11, GZMB, SLC4A4, RBM25, AK2, hCAP-D3, DDAH2, RBBP4, BAZ1A, PSAT1, HNRPD, BRIP1, TRMT5, KLHL24, ETNK1 WARS, SFRS2, EPASI, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, CDC40, SLC4A4, CXCL9, CXCL10, FAS, PLK4, CHEKI, KITLG, C1QBP, NDUFA9, 243 WHSCI, CA2, HNRPD, ME2, CXCL11, GZMB, 85% 83% 92% 79% 77% 72% TLK1, RBM25, AK2, hCAP-D3, BRRN1, CDC42BPA, RBBP4, BAZIA, AGPAT5, SEC10LI, FLJ13220, PBK, BRIPI, KLHL24, ETNK1, STATIC WARS, SFRS2, EPASI, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, ARF6, CDC40, SLC4A4, CXCL9, 244 RABIF, CXCL10, FAS, PLK4, CHEK1, KITLG, 81% 83% 88% 79% 81% 69% SLC25A1 1, C1QBP, NDUFA9, WHSCI, CA2, HNRPD, ME2, CXCL1 1, GZMB, IFT20, RBM25, CAMSAP1L1, BRRN1, CDC42BPA, BAZIA, AGPAT5, FLJ10534, DKFZp762E1312, PBK, 102 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN ETNK1 HNRPD, WARS, SFRS2, EPASI, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, TES, DCK, CDC40, SLC4A4, CXCL9, CXCL1O, PLK4, CHEK1, HNRPA3P1, 245 KITLG, C1QBP, NDUFA9, SLC25A11, WHSC1, 77% 86% 88% 76% 77% 76% CA2, ME2, GZMB, RBBP4, CXCL11, RBM25, AK2, NUP210, CAMSAP1L1, hCAP-D3, CDC42BPA, FAS, MARCH5, SEC10L1, PBK, ETNK1, STATIC WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GBPI, GMFB, DLGAP4, TYMS, TES, LMAN1, CDC40, SLC4A4, CXCL9, RABIF, CXCL1O, FAS, PLK4, HNRPA3P1, 246 SLC25A11, C1QBP, NDUFA9, KPNB1, WHSC1, 77% 83% 92% 79% 81% 79% C17orf25, CA2, ME2, FUT4, GZMB, TLK1, CXCL11, RBM25, CAMSAP1L1, DDAH2, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, HNRPD, BRIP1, ETNK1, STAT1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, TES, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, GTSEl, CXCL10, PLK4, KITLG, 247 C1QBP, NDUFA9, KPNB1, SLC25A11, WHSC1, 77% 83% 85% 79% 85% 72% C17orf25, CA2, ME2, IFT20, RBBP4, CXCL11, RBM25, AK2, CAMSAP1L1, CDC42BPA, FAS, AGPAT5, FLJ10534, MARCH5, SEC10L1, PBK, HNRPD, BRIPI, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, CDC40, CXCL9, GTSE1, RABIF, CXCL1O, FAS, PLK4, TRIM25, 248 C1QBP, NDUFA9, SLC25A11, WHSC1, C17or125, 77% 86% 88% 76% 81% 69% CA2, ME2, FUT4, GZMB, IFT20, RBBP4, CXCL11, SLC4A4, RBM25, BRRN1, AGPAT5, FLJ10534, MARCH5, FLJ13220, PSATI, TRMT5, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, MAD2L1, SLC4A4, CXCL9, GTSE1, CXCL10, FAS, PLK4, TRIM25, KITLG, NDUFA9, 249 KPNB1, WHSC1, C17orf25, CA2, ME2, FUT4, 92% 97% 88% 76% 85% 79% CXCL11, GZMB, IFT20, TLK1, RBM25, CAMSAP1L1, BRRN1, SOCS6, CDC42BPA, BAZIA, AGPAT5, MARCH5, SEC10L1, FLJ13220, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EPAS1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, ARF6, CDC40, CXCL9, CXCL10, FAS, CHEKI, TRIM25, NDUFA9, KPNB1, 250 SLC25A11, C17orf25, CA2, ME2, CXCL11, 92% 90% 92% 76% 85% 79% IFT20, TLK1, SLC4A4, RBM25, AK2, BRRN1, ATP5A1, DDAH2, BAZIA, AGPAT5, MARCH, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, STAT1 251 WARS, EPASI, STAT1, EIF4E, SFPQ, PRDX3, 77% 90% 92% 76% 85% 72% MTBFD2, PSNM2, TKI, GM1B, DLGAP4, 103 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN TYMS, LMAN1, ARF6, SLC4A4, CXCL9, IRF8, GTSE1, CXCL1O, FAS, PLK4, HNRPA3P1, SLC25A1 1, C1QBP, NDUFA9, CA2, HNRPD, ME2, FUT4, CXCL1 1, GZMB, IFT20, TLK1, RBM25, AK2, ATP5A1, SOCS6, DDAH2, RBBP4, AGPAT5, MARCH, SEC10LI, FLJ13220, BRIPI, TRMT5 WARS, SFRS2, EPASI, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, CDC40, SLC4A4, GTSE1, RABIF, CXCL10, FAS, PLK4, 252 HNRPA3P1, C1QBP, SLC25A11, WHSC1, HNRPD, ME2, FUT4, CXCL11, IFT20, TLK1, 65% 83% 77% 90% 73% 76% RBM25, AK2, NUP210, BRRN1, ATP5A1, AGPAT5, FLJI0534, DKFZp762E1312, SEC10L1, FLJ13220, PBK, TRMT5, KLHL24, ETNK1, STATIC HNRPD, WARS, EPASI, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, DCK, SLC4A4, CXCL9, 253 CXCL10, FAS, PLK4, C1QBP, NDUFA9, KPNB1, 73% 83% 85% 79% 81% 76% SLC25A1 1, WHSC1, C17orf25, CA2, ME2, FUT4, CXCL11, RBBP4, TLK1, RBM25, CAMSAP1L1, ATP5A1, MARCH5, SEC1OL1, PBK, PSAT1, BRIP1, TRMT5, KLHL24, ETNK1 HNRPD, WARS, EPAS1, EIF4E, MTHIFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, ARF6, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, PLK4, CHEKI, HNRPA3P1, 254 C1QBP, NDUFA9, SLC25A1 1, WHSC1, C17orf25, 77% 76% 92% 86% 88% 79% CA2, ME2, FUT4, IFT20, RBBP4, CXCL11, RBM25, NUP210, hCAP-D3, SFRS2, DDAH2, BAZIA, AGPAT5, FLJ10534, DKFZp762E1312, SEC10L1, FLJ13220, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, CXCL1O, PLK4, CHEKI, TRIM25, KITLG, ClQBP, 255 NDUFA9, WHSC1, C17orf25, CA2, ME2, 81% 79% 85% 79% 85% 76% CXCL11, SLC4A4, RBM25, AK2, NUP210, DDAH2, FAS, BAZIA, AGPAT5, FLJ10534, MARCH5, DKFZp762E1312, SEC10L1, PBK, PSATI, BRIP1, KLHL24, STATIC WARS, SFRS2, EPASI, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, CDC40, SLC4A4, 256 CXCL9, RABIF, CXCL1O, FAS, PLK4, CHEKI, 77% 83% 85% 79% 81% 83% TRIM25, KITLG, SLC25A1 1, C1QBP, NDUFA9, C17orf25, CA2, ME2, TLK1, RBM25, NUP210, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, PSAT1, HNRPD, BRIP1, TRMT5, KLHL24 WARS, SFRS2, EIF4E, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, LMANI, MAD2L1, CDC40, CXCL9, CXCL10, FAS, 257 CHEKI, HNRPA3P1, KITLG, SLC25A11, C1QBP, 73% 86% 88% 83% 77% 72% NDUFA9, KPNB1, WHSC1, CA2, HNRPD, ME2, GZMB, TLK1, SLC4A4, CXCL1 1, RBM25, AK2, CAMSAP1L1, DDAH2, AGPAT5, FLJ10534, 104 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1INN MARCH5, DKFZp762E1312, PBK, PSATI, BRIP1, TRMT5, KLHL24, ETNK1, STATIC WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, ARF6, CDC40, CXCL9, CXCL10, FAS, PLK4, CHEKI, HNRPA3P1, SLC25A1 1, C1QBP, 258 NDUFA9, WHSC1, C17or25, HNRPD, ME2, 77% 83% 73% 86% 73% 76% CXCL1 1, IFT20, RBBP4, SLC4A4, RBM25, AK2, ATP5A1, SOCS6, FLJ10534, MARCH5, DKFZp762E1312, SECIOL1, FLJ13220, PBK, PSATI, BRIP1, TRMT5, ETNK1, STATIC HNRPD, WARS, EPAS1, PAICS, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, CDC40, CXCL9, RABIF, CXCL10, FAS, PLK4, HNRPA3P1, TRIM25, SLC25A11, C1QBP, 259 NDUFA9, WHSC1, CA2, ME2, CXCL11, GZMB, 85% 93% 92% 72% 77% 72% IFT20, RBBP4, TLK1, RBM25, AK2, CAMSAP1L1, ATP5A1, CDC42BPA, DDAH2, BAZIA, AGPAT5, FLJ10534, MARCH, SEC1OL1, FLJ13220, PBK, PSAT1, BRIP1, ETNK1, STATIC HNRPD, WARS, SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, MAD2L1, CDC40, CXCL9, GTSE1, RABIF, CXCL10, PLK4, CHEKI, HNRPA3P1, 260 TRIM25, NDUFA9, SLC25A1 1, WHSC1, 77% 79% 85% 76% 85% 69% C17orf25, CA2, ME2, FUT4, CXCL11, IFT20, SLC4A4, RBM25, AK2, NUP210, ATP5A1, SOCS6, FAS, AGPAT5, FLJ10534, MARCH, SEC1OL1, PBK, PSATI, BRIP1, ETNK1, STATIC HNRPD, WARS, SFRS2, STATIC, MTHFD2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, ARF6, SLC4A4, CXCL9, GTSE1, CXCL10, FAS, HNRPA3P1, TRIM25, SLC25A11, C1QBP, 261 NDUFA9, KPNB1, WHSC1, C17orf25, CA2, ME2, 85% 83% 88% 72% 77% 76% CXCL11, GZMB, IFT20, RBM25, hCAP-D3, ATP5A1, SOCS6, DDAH2, BAZIA, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIP1, ETNK1 HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, CDC40, CXCL9, CXCL1O, FAS, PLK4, CHEKI, HNRPA3P1, 262 KITLG, C1QBP, NDUFA9, SLC25A11, WHSC1, 77% 79% 85% 79% 85% 76% C17orf25, CA2, ME2, CXCL11, IFT20, SLC4A4, RBM25, AK2, ATP5A1, SOCS6, BAZIA, AGPAT5, FLJ10534, SEC1OL1, PBK, PSAT1, BRIPI, KLHL24, ETNK1, STAT1 HNRPD, WARS, SFRS2, EPASI, STAT1, EIF4E, PRDX3, PSME2, MCM6, GBP1, GMFB, DLGAP4, USP4, CTSS, ARF6, CDC40, SLC4A4, CXCL9, GTSE1, RABIF, CXCL1O, FAS, CHEK1, 263 HNRPA3P1, KITLG, CIQBP, NDUFA9, KPNB1, 81% 83% 88% 79% 81% 79% WHSCI, CA2, ME2, CXCL1 1, RBM25, CDC42BPA, RBBP4, AGPAT5, MARCH5, SEC10LI, FLJ13220, PBK, PSATI, TRMT5, KLHL24 105 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN WARS, SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GBP1, TKI, GMFB, DLGAP4, TYMS, CTSS, LMAN1, CDC40, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, PLK4, TRIM25, 264 SLC25A11, C1QBP, NDUFA9, WHSC1, CA2, 88% 86% 88% 83% 85% 79% HNRPD, ME2, CXCL1 1, GZMB, TLK1, RBM25, AK2, hCAP-D3, ATP5A1, CDC42BPA, BAZ1A, AGPAT5, MARCH5, SEC1OL1, PBK, TRMT5, KLHL24, STAT1 HNRPD, WARS, EPASI, PAICS, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, ARF6, CDC40, SLC4A4, CXCL9, IRF8, CXCL10, FAS, 265 PLK4, CHEKI, TRIM25, KITLG, C1QBP, 92% 90% 85% 76% 69% 76% NDUFA9, KPNB1, SLC25A1 1, WHSC1, ME2, GZMB, TLK1, CXCL1 1, RBM25, AK2, CAMSAP1L1, AGPAT5, FLJ10534, SEC10L1, PBK, BRIP1, KLHL24, STAT1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, MAD2L1, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, PLK4, TRIM25, C1QBP, 266 NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, 77% 86% 88% 76% 85% 79% ME2, CXCL1 1, GZMB, RBM25, AK2, ATP5A1, RBBP4, AGPAT5, MARCH5, SEClOL1, PBK, HNRPD, BRIP1, TRMT5, KLHL24, ETNK1, STAT1 WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, LMAN1, DCK, ARF6, CDC40, SLC4A4, CXCL9, IRF8, GTSE1, CXCL1O, FAS, CHEK1, SLC25A11, 267 C1QBP, NDUFA9, WHSC1, C17orf25, CA2, ME2, 85% 83% 85% 79% 81% 76% CXCL11, IFT20, RBM25, AK2, NUP210, SOCS6, CDC42BPA, SFRS2, RBBP4, BAZIA, FLJ10534, MARCH5, FLJ13220, PBK, PSATI, HNRPD, KLHL24, STAT1 HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, USP4, ARF6, CDC40, SLC4A4, IRF8, GTSE1, CXCL10, FAS, HNRPA3P1, 268 TRIM25, KITLG, NDUFA9, SLC25A1 1, CA2, 88% 93% 92% 76% 81% 72% ME2, CXCL11, GZMB, TLK1, RBM25, AK2, hCAP-D3, CDC42BPA, AGPAT5, FLJ10534, MARCH, SEC10L1, FLJ13220, PBK, PSATI, BRIPI, TRMT5, STATIC HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, ARF6, CDC40, SLC4A4, CXCL9, GTSE1, CXCL10, HNRPA3P1, KITLG, 269 ClQBP, NDUFA9, SLC25A1 1, WHSC1, C17orf25, 81% 79% 92% 76% 81% 69% CA2, ME2, FUT4, CXCL11, GZMB, RBM25, AK2, CDC42BPA, FAS, RBBP4, BAZIA, SEC1OL1, FLJ13220, PBK, PSATI, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, 270 MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, ARF6, MAD2L1, CDC40, CXCL9, 88% 86% 88% 79% 85% 72% IRF8, GTSE1, CXCL1O, FAS, CHEKI, 106 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN HNRPA3P1, TRIM25, KITLG, SLC25A1 1, NDUFA9, KPNB1, WHSC1, CA2, ME2, FUT4, CXCL1 1, GZMB, RBM25, AK2, CDC42BPA, BAZ1A, AGPAT5, DKFZp762E1312, SEC1OL1, PBK, TRMT5, KLHL24, ETNK1, STAT1 WARS, SFRS2, EPASI, STATIC, EIF4E, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, 271 GTSE1, CXCL10, PLK4, ClQBP, NDUFA9, 77% 69% 92% 79% 81% 69% SLC25A11, WHSC1, CA2, HNRPD, ME2, FUT4, GZMB, RBM25, AK2, ATP5A1, CDC42BPA, FAS, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, BRIPI, TRMT5, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, DCK, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, HNRPA3P1, 272 KITLG, C1QBP, NDUFA9, SLC25A1 1, CA2, 73% 83% 92% 83% 85% 76% ME2, FUT4, IFT20, RBBP4, TLK1, CXCL11, RBM25, BRRN1, CDC42BPA, AGPAT5, FLJ10534, MARCH5, SEC1OL1, PBK BRIPI, TRMT5, KLHL24, ETNK1, STAT1 WARS, SFRS2, EPASI, STATIC, EIF4E, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, ARF6, CXCL9, IRF8, RABIF, 273 CXCL1O, FAS, PLK4, CHEK1, KITLG, SLC25A1I, C1QBP, NDUFA9, WHSC1, CA2, 88% 83% 85% 83% 77% 79% ME2, CXCL11, IFT20, RBBP4, TLK1, RBM25, ATP5A1, CDC42BPA, FLJ13220, PBK, HNRPD, BRIPI, TRMT5, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, TES, DCK, MAD2L1, CXCL9, CXCL10, FAS, PLK4, HNRPA3P1, KITLG, SLC25A1 1, 274 NDUFA9, WHSC1, C17orf25, CA2, ME2, IFT20, 81% 86% 88% 83% 85% 76% RBBP4, CXCL11, SLC4A4, RBM25, NUP210, CAMSAP1L1, BRRN1, CDC42BPA, DDAIH2, AGPAT5, FLJ10534, MARCH5, SEC10L1, FLJ13220, PBK, TRMT5, KLHL24, ETNK1, STATIC WARS, SFRS2, PAICS, EIF4E, MTHFD2, PSME2, MCM6, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, CDC40, CXCL9, CXCLI0, PLK4, TRIM25, KITLG, SLC25A11, 275 C1QBP, NDUFA9, C17orf25, HNRPD, ME2, 73% 86% 77% 83% 69% 79% CXCL1 1, IFT20, TLK1, SLC4A4, RBM25, hCAP D3, ATP5A1, DDAH2, FAS, AGPAT5, FLJ10534, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, KLHL24, STATIC HNRPD, WARS, SFRS2, STAT1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, ARF6, CDC40, 276 CXCL9, IRF8, CXCL10, FAS, PLK4, TRIM25, 85% 79% 88% 79% 81% 79% KITLG, C1QBP, NDUFA9, SLC25A1 1, WHSC1, CA2, ME2, CXCL11, GZMB, RBBP4, TLK1, RBM25, AK2, NUP210, ATP5A1, AGPAT5, MARCH5, SEC1OL1, PBK, BRIP1, TRMT5 107 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN HNRPD, WARS, SFRS2, EPAS1, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, DCK, SLC4A4, CXCL9, GTSE1, CXCL1O, PLK4, 277 CHEKI, TRIM25, C1QBP, NDUFA9, KPNB1, 81% 83% 88% 76% 77% 69% WHSC1, C17orf25, ME2, CXCL11, RBM25, BRRN1, ATP5A1, CDC42BPA, DDAH2, FAS, AGPAT5, MARCH5, PBK, BRIP1, TRMT5, KLHL24, ETNK1 WARS, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, MCM6, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, MAD2L1, CDC40, SLC4A4, CXCL9, 278 RABIF, CXCL10, FAS, KITLG, SLC25A 1, C1QBP, NDUFA9, C17orf25, CA2, HNRPD, ME2, 77% 72% 88% 83% 77% 79% GZMB, TLK1, CXCL11, RBM25, BRRN1, CDC42BPA, SFRS2, DDAH2, AGPAT5, SEC1OL1, PBK, PSAT1, BRIPI, TRMT5, KLHL24 HNRPD, WARS, EPASI, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, TES, DCK, ARF6, CDC40, SLC4A4, CXCL9, RABIF, CXCL10, FAS, 279 TRIM25, NDUFA9, SLC25A11, WHSC1, 77% 86% 92% 76% 77% 76% C17orf25, CA2, ME2, GZMB, TLK1, CXCL1 1, RBM25, AK2, hCAP-D3, CDC42BPA, DDAH2, RBBP4, FLJ10534, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, KLHL24 WARS, SFRS2, STAT1, EIF4E, MTHFD2, PSME2, MCM6, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, LMAN1, ARF6, CDC40, SLC4A4, CXCL9, CXCL1O, FAS, PLK4, 280 KITLG, C1QBP, KPNB1, WHSC1, CA2, ME2, 81% 79% 92% 79% 85% 72% FUT4, GZMB, CXCL1 1, RBM25, AK2, CDC42BPA, RBBP4, BAZ1A, AGPAT5, MARCH5, SEC1OL1, PBKY, HNRPD, BRIPI, KLHL24, ETNK1 HNRPD, WARS, SFRS2, EPASI, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, DCK, CDC40, 281 SLC4A4, CXCL9, IRF8, CXCL10, TRIM25, SLC25A11, C1QBP, NDUFA9, KPNBT, WuISCI, 85% 79% 77% 86% 73% 76% ME2, CXCL11, TLK1, RBM25, hCAP-D3, CDC42BPA, FAS, BAZIA, AGPAT5, SECIOL1, FLJ13220, PBK, TRMT5, ETNKI HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, MAD2L1, SLC4A4, CXCL9, CXCL10, FAS, CHEKI, SLC25A11, 282 C1QBP, NDUFA9, KPNB1, WHSC1, C17orf25, 77% 83% 88% 83% 88% 86% CA2, ME2, FUT4, CXCL1 1, TLK1, RBM25, hCAP-D3, ATP5A1, CDC42BPA, DDAH2, AGPAT5, FLJ10534, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, TRMT5, STATIC WARS, SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, 283 TYMS, USP4, TES, ARF6, CDC40, CXCL9, 81% 83% 85% 76% 85% 72% CXCL10, FAS, PLK4, TRIM25, SLC25A1 1, C1QBP, NDUFA9, WHSC1, C17orf25, CA2, ME2, FUT4, IFT20, SLC4A4, CXCL 11, RBM25, AK2, 108 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN BRRN1, ATP5A1, CDC42BPA, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, HNRPD, BRIP1, TRMT5, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, SLC4A4, CXCL9, IRF8, CXCL10, FAS, KITLG, ClQBP, NDUFA9, SLC25A11, WHSC1, C17orf25, CA2, ME2, 284 GZMB, CXCL11, RBM25, AK2, hCAP-D3, 81% 76% 88% 79% 85% 72% CDC42BPA, DDAH2, RBBP4, AGPAT5, MARCH5, DKFZp762E1312, SEC10L1, FLJ13220, PBK, BRIPI, TRMT5, KLHL24, STAT1 WARS, SFRS2, EPAS1, STAT1, ELF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, ARF6, CDC40, SLC4A4, CXCL9, CXCL10, FAS, CHEKI, TRIM25, 285 SLC25A11, ClQBP, Cl7orf25, CA2, ME2, GZMB, 85% 86% 92% 76% 81% 72% IFT20, RBBP4, CXCL1 1, RBM25, AK2, NUP2 10, SOCS6, DDAH2, AGPAT5, FLJ10534, MARCH5, DKFZp762E1312, SEC10L1, PBK, HNRPD, TRMT5 WARS, EPAS1, STAT1, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, DLGAP4, TYMS, MAD2L1, CDC40, CXCL9, IRF8, CXCL10, FAS, TRIIM25, KITLG, C1QBP, NDUFA9, SLC25AI 1, 286 WHSC1, C17orf25, HNRPD, ME2, CXCL11, 73% 76% 81% 79% 73% 66% IFT20, RBBP4, SLC4A4, RBM25, AK2, NUP210, SOCS6, CDC42BPA, BAZ1A, AGPAT5, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, TRMT5 WARS, SFRS2, EPAS1, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, CTSS, ARF6, MAD2L1, CDC40, CXCL9, CXCL1O, FAS, TRIM25, 287 SLC25A1 1, C1QBP, NDUFA9, KPNB1, WHSC1, 88% 90% 88% 79% 77% 79% C17orf25, CA2, HNRPD, ME2, CXCL1 1, GZMB, IFT20, TLK1, SLC4A4, RBM25, CAMSAP1L1, hCAP-D3, RBBP4, BAZ1A, AGPAT5, MARCH5, FLJ13220, PBK, TRMT5, ETNK1, STATIC HNRPD, WARS, SFRS2, EPASI, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, ARF6, CDC40, CXCL9, 288 CXCL10, FAS, SLC25A11, NDUFA9, WHSC1, 81% 90% 85% 76% 85% 69% C17orf25, CA2, ME2, CXCL11, IFT20, SLC4A4, RBM25, AK2, SOCS6, DDAH2, RBBP4, BAZ1A, DKFZp762E1312, FLJ13220, PBK, PSATI, BRIP1, ETNK1 WARS, SFRS2, EPAS1, STAT1, PAICS, EIF4E, PRDX3, MT1FD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, CDC40, CXCL9, IRF8, RABIF, CXCL1O, FAS, TRIM25, 289 SLC25A11, C1QBP, WHSC1, C17orf25, CA2, 77% 86% 88% 83% 73% 69% HNRPD, ME2, CXCL1 1, GZMB, TLK1, RBM25, CAMSAP1L1, hCAP-D3, CDC42BPA, BAZIA, AGPAT5, MARCH5, DKFZp762E1312, FLJ13220, PBK, PSAT1, BRIPI, KLHL24 290 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, 85% 83% 85% 83% 81% 72% 109 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, ARF6, MAD2L1, SLC4A4, CXCL9, IRF8, CXCL10, FAS, TRIM25, SLC25A1 1, NDUFA9, KPNB1, WHSC1, C17orf25, CA2, ME2, GZMB, IFT20, RBBP4, CXCL1 1, RBM25, AK2, BRRN1, CDC42BPA, AGPAT5, FLJ10534, MARCH, SEC1OL1, FLJ13220, PBK, HNRPD, BRIPI, KLHL24, ETNK1, STATIC HNRPD, WARS, SFRS2, EPAS1, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, ARF6, MAD2L1, 291 CDC40, CXCL9, CXCL1O, FAS, PLK4, CHEKI, 85% 86% 92% 79% 85% 86% KITLG, SLC25A11, NDUFA9, KPNB1, CA2, ME2, FUT4, CXCL11, GZMB, TLK1, SLC4A4, RBM25, ATP5A1, DDAH2, MARCH5, DKFZp762E1312, PBK, BRIP1, KLHL24 WARS, SFRS2, EPAS1, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, TKI, GMFB, DLGAP4, TYMS, USP4, CTSS, CXCL9, IRF8, RABIF, CXCL1O, FAS, PLK4, TRIM25, ClQBP, 292 NDUFA9, SLC25A11, C17orf25, CA2, HNRPD, 81% 83% 85% 72% 69% 76% ME2, CXCL1 1, GZMB, SLC4A4, RBM25, ATP5A1, CDC42BPA, DDAH2, MARCH5, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, KLHL24, ETNK1, UBD, GTSE1, MYO1B, TMED5, RBBP8 HNRPD, WARS, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, MAD2L1, CXCL9, IRF8, CXCL1O, FAS, SLC25A11, NDUFA9, WHSCI, ME2, CXCL11, 293 IFT20, RBBP4, SLC4A4, RBM25, AK2, NUP210, 81% 79% 77% 79% 69% 72% CAMSAP1L1, ATP5A1, DDAH2, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIP1, STAT1, FLJ22471, LAPTM5, DEPDC1, INDO, YDD19 WARS, SFRS2, PSME2, GMFB, DLGAP4, TYMS, TES, CDC40, CXCL9, CXCL10, HNRPA3P1, C1QBP, SLC25A11, WHSCI, 294 C17orf25, CA2, ME2, TLK1, SLC4A4, CXCL11, 73% 79% 88% 79% 85% 76% AK2, hCAP-D3, DDAH2, FAS, AGPAT5, FLJ10534, PSATI, HNRPD, BRIPI, KLHL24, STATIC, IVD WARS, SFRS2, EPASI, EIF4E, SFPQ, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, CDC40, SLC4A4, CXCL9, IRF8, RABIF, CXCL1O, FAS, PLK4, CHEK1, HNRPA3P1, 295 TRIM25, SLC25A11, NDUFA9, KPNB1, WHSC1, 85% 86% 85% 76% 73% 76% CA2, HNRPD, ME2, GZMB, IFT20, CXCL1 1, RBM25, hCAP-D3, BAZIA, AGPAT5, MARCH5, PBK, BRIPI, KLHL24, ETNK1, STAT1, TACC3, IL2RB, AK2 HNRPD, WARS, SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CDC40, SLC4A4, CXCL9, CXCL1O, 296 HNRPA3P1, KITLG, C1QBP, NDUFA9, 81% 86% 92% 86% 85% 76% SLC25A1 1, WHSCI, CA2, ME2, FUT4, CXCL1 1, IFT20, RBBP4, RBM25, AK2, DDAH2, FAS, FLJ10534, SEC10L1, FLJ13220, PBK, BRIPI, 110 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN TRMT5, KLHL24, STAT1, FEM1C, ITGB5 WARS, EIF4E, PSME2, GMFB, DLGAP4, TYMS, USP4, CDC40, SLC4A4, CXCL10, TRIM25, C1QBP, NDUFA9, SLC25A1 1, CA2, ME2, 297 CXCL11, RBM25, CAMSAP1L1, ATP5A1, 77% 79% 73% 86% 81% 86% SOCS6, FLJ10534, DKFZp762E1312, SEC10L1, HNRPD, STATIC, LMAN1, LOC92249, NFS1 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, DCK, MAD2L1, CXCL9, GTSE1, CXCL1O, FAS, HNRPA3P1, KITLG, ClQBP, 298 NDUFA9, SLC25A11, WHSC1, CA2, HNRPD, 81% 76% 81% 72% 77% 76% ME2, FUT4, CXCL11, SLC4A4, RBM25, CDC42BPA, DDAH2, RBBP4, FLJ10534, MARCH5, SEC1OL1, FLJ13220, PBK, BRIPI, ETNK1, STATIC, ZWINT, ZG16, TPRT, PURA HNRPD, WARS, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, 299 MAD2L1, SLC4A4, CXCL9, CXCL10, FAS, NDUFA9, WHSC1, ME2, GZMB, TLK1, CXCL11, 85% 79% 81% 69% 77% 72% RBM25, AGPAT5, FLJ13220, KLHL24, SLAMF8, PBX1, CAP350 HNRPD, WARS, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, GBPI, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, ARF6, CXCL9, CXCL10, FAS, TRIM25, KITLG, ClQBP, 300 NDUFA9, KPNB1, SLC25A1 1, WHSC1, CA2 77% 79% 85% 76% 85% 79% ME2, FUT4, CXCL1 1, GZMB, IFT20, SLC4A4, RBM25, BRRN1, ATP5A1, SFRS2, DDAH2, RBBP4, SEC10L1, FLJ13220, PBK, PSATI, KLHL24, ETNK1, FLJ20273, VAPB, LARP4, CD74, BTN2A2 WARS, SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, CDC40, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, PLK4, CHEKI, TRIM25, 301 KITLG, SLC25A11, C1QBP,NDUFA9, WHSC1, 81% 76% 88% 69% 77% 69% HNRPD, ME2, CXCL11, GZMB, RBBP4, RBM25, CAMSAP1L1, BRRN1, CDC42BPA, AGPAT5, FLJ10534, SEC10L1, PBK, BRIP, KLHL24, ETNK1, STATIC, H2AFZ, PGGT1B WARS, EIF4E, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, CDC40, SLC4A4, CXCL1O, 302 FAS, CHEKI, HNRPA3P1, KITLG, SLC25AI1, 85% 86% 88% 83% 81% 79% CA2, ME2, FUT4, CXCL1 1, IFT20, TLK1, RBM25, AK2, SFRS2, TRMT5, KLHL24, STATIC, FKBP9 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TKI, DLGAP4, TYMS, TES, MAD2L1, CDC40, CXCL9, CXCL1O, FAS, PLK4, CHEKI, TRIM25, C1QBP, 303 NDUFA9, WHSC1, CA2, ME2, CXCL11, GZMB, 77% 79% 88% 79% 81% 76% RBBP4, SLC4A4, RBM25, CAMSAP1L1, DDAH2, AGPAT5, MARCH5, SEC1OL1, PBK, BRIPI, TRMT5, ETNK1, STATIC, CHAF1A, ITGB5, HNRPDL 304 HNRPD, WARS, SFRS2, MTHFD2, PSME2, TK1, 81% 79% 81% 83% 81% 72% 111 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN GMFB, DLGAP4, TYMS, LMAN1, DCK, MAD2L1, CXCL9, CXCL1O, FAS, KITLG, KPNB1, SLC25A11, WHSC1, ME2, CXCL11, IFT20, SLC4A4, RBM25, BRRN1, ATP5A1, CDC42BPA, BAZIA, MARCH5, SEC10L1, PBK, PSAT1, BRIP1, KLHL24, STAT1, RBM28 HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CDC40, CXCL9, CXCL10, PLK4, HNRPA3P1, TRIM25, 305 SLC25A11, KPNB1, ME2, SLC4A4, RBM25, 77% 83% 77% 83% 88% 79% hCAP-D3, FAS, RBBP4, BAZIA, DKFZp762E1312, SEC1OL1, KLHL24, STATIC, PSME1, BUB3, SOCS6 WARS, EPAS1, STAT1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, CTSS, ARF6, SLC4A4, CXCL9, RABIF, CXCL10, FAS, PLK4, KITLG, SLC25A11, C1QBP, 306 NDUFA9, KPNB1, WHSC1, CA2, HNRPD, ME2, 73% 79% 85% 79% 81% 76% FUT4, CXCL1 1, IFT20, RBM25, CAMSAPIL1, SOCS6, DDAH2, AGPAT5, FLJ10534, MARCH5, SEC10L1, FLJ13220, PBK, BRIPI, KLHL24, ETNK1, RPS2, CHAF1A, LGALS3BP WARS, SFRS2, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CXCL9, GTSE1, RABIF, 307 CXCL10, HNRPA3P1, TRIM25, KITLG, C1QBP, 85% 93% 85% 83% 81% 83% NDUFA9, WHSC1, CA2, ME2, FUT4, RBM25, hCAP-D3, ATP5A1, DDAH2, FAS, STAT1, CDCA8, HMGB3 WARS, MTHFD2, PSME2, GBPI, MAD2L1, CXCL9, IRF8, CXCL1O, CHEKI, KITLG, ME2, 308 CXCL11, IFT20, RBM25, AK2, ATP5A1, FAS, 81% 76% 81% 83% 77% 69% AGPAT5, SEC1OL1, FLJ13220, HNRPD, KLHL24, ETNK1, STAT1, ECGF1 WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CDC40, SLC4A4, CXCL9, GTSE1, CXCL1O, FAS, PLK4, CHEKI, KITLG, C1QBP, 309 NDUFA9, SLC25A11, WHSC1, C17orf25, ME2, 81% 83% 88% 76% 73% 76% FUT4, CXCL1 1, IFT20, RBBP4, RBM25, AK2, NUP210, BRRN1, CDC42BPA, AGPAT5, FLJ10534, MARCH5, SEC1OL1, FLJ13220, PBK, TRMT5, ETNK1, STAT1, SELL, GART WARS, SFRS2, EPASI, STAT1, EIF4E, SFPQ, MTHFD2, PSME2, TKI, GMFB, DLGAP4, TYMS, USP4, CTSS, ARF6, CDC40, CXCL9, GTSE1, CXCL10, FAS, PLK4, CHEKI, TRIM25, 310 SLC25A11, C1QBP, NDUFA9, WHSC1, ME2 73% 72% 85% 83% 69% 72% FUT4, CXCL11, IFT20, RBBP4, SLC4A4, RBM25, hCAP-D3, DDAH2, AGPAT5, FLJ10534, MARCH5, SEC10L1, FLJ13220, PSAT1, HNRPD, BRIPI, KLHL24, ETNK1, WFDC1, YTHDF3, K ALPHA-1, PAWR HNRPD, WARS, SFRS2, STATIC, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, 311 TYMS, TES, LMAN1, MAD2L1, CDC40, CXCL9, 81% 83% 88% 83% 73% 79% IRF8, CXCL1O, PLK4, HNRPA3P1, KITLG, C1QBP, NDUFA9, SLC25A1 1, WHSC1, ME2, 112 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN FUT4, CXCL1 1, IFT20, RBM25, BRRN1, CDC42BPA, FAS, AGPAT5, DKFZp762E1312, SEC1OL1, FLJ13220, PBK, BRIP1, KLHL24, SMC2L1, IRFI WARS, EPASI, STAT1, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, CXCL9, IRF8, CXCL10, KITLG, 312 C1QBP, NDUFA9, SLC25A11, ME2, SLC4A4, 73% 79% 81% 79% 77% 76% RBM25, hCAP-D3, SOCS6, FAS, RBBP4, BAZIA, AGPAT5, PSAT1, BRIPI, ETNK1, LPP, PPM1D, LAP3, TXNDC WARS, EIF4E, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, CXCL10, SLC25A1 1, 313 C1QBP, NDUFA9, KPNB1, C17orf25, CA2, ME2, 77% 76% 85% 79% 77% 83% RBBP4, SLC4A4, RBM25, FAS, SEC1OL1, PBK, FNRPD, ETNK1, STAT1, KIAA0828, SPCS3, NARS HNRPD, WARS, SFRS2, EPAS1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, CDC40, SLC4A4, CXCL9, IRF8, CXCL1O, FAS, PLK4, 314 KITLG,C1QBP,NDUFA9,SLC25A11,WHSC1, 81% 76% 85% 79% 81% 79% CA2, ME2, GZMB, CXCL11, RBM25, CAMSAP1L1, CDC42BPA, FLJ10534, MARCH5, FLJ13220, PBK, PSAT1, BRIPI, KLHL24, STATIC, NUP160, HLA-E WARS, EIF4E, SFPQ, PRDX3, MTHFD2, MCM6, GMFB, DLGAP4, TYMS, CDC40, CXCL9, CXCL10, CHEK1, HNRPA3P1, C1QBP, 315 SLC25A11, WHSC1, CA2, ME2, CXCL11, 73% 79% 85% 83% 77% 72% SLC4A4, RBM25, AK2, SFRS2, FAS, MARCH5, FLJ13220, KLHL24, ETNK1, STATIC, SOCS1 WARS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, USP4, DCK, CDC40, CXCL9, CXCL1O, 316 FAS, SLC25A11, C1QBP, KPNB1, WHSC1, CA2, 81% 83% 81% 79% 85% 76% ME2, FUT4, CXCL11, RBM25, DDAH2, SEC10L1, PBK, HNRPD, TRMT5, KLHL24, STATIC, PPA2, GTSEl, TNFRSF1 1A, RYK WARS, SFRS2, EPAS1, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, CDC40, SLC4A4, CXCL9, IRF8, CXCL10, PLK4, CHEK1, 317 SLC25A11, ClQBP, KPNB1, WHSC1, CA2, ME2, 77% 90% 85% 79% 85% 83% GZMB, TLK1, CXCL11, RBM25, hCAP-D3, FAS, RBBP4, FLJ10534, MARCH5, HNRPD, STATIC, KIF2C, HIATI WARS, EIF4E, PRDX3, PSME2, GBP1, TYMS, LMAN1, CXCL9, CXCL10, FAS, CHEK1, 318 SLC25A11, NDUFA9, CA2, ME2, RBBP4, TLK1, 69% 83% 77% 86% 81% 83% CXCL11, SLC4A4, BRRN1, PBK, HNRPD, STAT1, TGFB2 WARS, SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, DLGAP4, TYMS, LMAN1, SLC4A4, CXCL9, CXCL10, PLK4, 319 SLC25AI1, WHSC1, C17orf25, CA2, ME2, 92% 90% 88% 79% 73% 79% CXCL1 1, GZMB, IFT20, RBM25, NUP210, CAMSAP1L1, ATP5A1, FAS, RBBP4, AGPAT5, FLJ10534, PBK, PSATI, HNRPD, STATIC, HLA 113 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN DMB SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, CXCL10, FAS, PLK4, CHEKI, 320 HNRPA3P1, TRIM25, SLC25A11, C1QBP, NDUFA9, CA2, ME2, CXCL11, SLC4A4, RBM25, 73% 86% 73% 76% 81% 79% ATP5A1, FLJ13220, PSAT1, BRIP1, STATIC, RIFI, SCC-112, U2AF2 HNRPD, WARS, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, DCK, CDC40, SLC4A4, CXCL9, CXCL10, FAS, PLK4, TRIM25, 321 SLC25A11, NDUFA9, WHSC1, C17orf25, CA2, 77% 83% 81% 79% 81% 76% ME2, FUT4, CXCL11, IFT20, RBM25, AK2, BRRN1, SFRS2, DDAH2, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, KLHL24, CD8A, GTF2H2, Cl4orfl56, BIRC5 HNRPD, WARS, SFRS2, EPASI, STAT1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, 322 CXCL9, RABIF, CXCL1O, FAS, TRIM25, NDUFA9, KPNB1, WHSC1, CA2, ME2, RBBP4, 77% 79% 81% 83% 88% 76% SLC4A4, RBM25, NUP210, hCAP-D3, SOCS6, BAZIA, PBK, PSATI, BRIP1, KLHL24, MAX, HADHSC WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, ARF6, MAD2L1, CDC40, CXCL9, IRF8, CXCL1O, 323 TRIM25, SLC25A1 1, C1QBP, NDUFA9, CA2, 88% 83% 88% 76% 85% 79% ME2, CXCL11, GZMB, SLC4A4, RBM25, AK2, NUP210, BRRN1, ATP5A1, DDAH2, FAS, MARCH5, SEC10L1, PBK, HNRPD, ETNK1, STATIC, AP1G1 WARS, STAT1, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, ARF6, MAD2L1, CDC40, CXCL9, CXCL1O, FAS, PLK4, TRIM25, KITLG, C1QBP, NDUFA9, KPNB1, 324 SLC25A11, WHSC1, CA2, HNRPD, ME2, FUT4, 73% 76% 81% 83% 85% 86% CXCL11, RBM25, CAMSAP1L1, hCAP-D3, BRRN1, ATP5A1, SOCS6, RBBP4, SEC10L1, PBK, BRIP, KLHL24, ETNK1, MIS12, RBMS3, RUNX1, TTC19 HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, MAD2L1, 325 CXCL10, FAS, HNRPA3P1, NDUFA9, SLC25A11, CA2, ME2, GZMB, CXCL11, hCAP- 85% 76% 92% 76% 85% 76% D3, RBBP4, BAZIA, AGPAT5, FLJ10534, ETNK1, STATIC, JAK2, RNGTT WARS, PAICS, EIF4E, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, TES, ARF6, CDC40, CXCL9, RABIF, CXCL10, FAS, TRIM25, 326 KITLG, C1QBP, NDUFA9, SLC25A1 1, WHSC1, 73% 76% 81% 79% 77% 66% ME2, FUT4, CXCL11, SLC4A4, RBM25, CAMSAPiLl, hCAP-D3, CDC42BPA, AGPAT5, PBK, PSAT1, HNRPD, BRIP1, STATIC, CDC2, ATP13A3, ZC3HAV1, FANCA 327 WARS, EIF4E, MTHFD2, PSME2, TK1, GMFB, 77% 79% 85% 79% TYMS, CXCL9, CXCL10, FAS, SLC25A1 1, '7% 9 85% 79% 69% 79% 114 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN WHSC1, C17orf25, CA2, ME2, RBM25, NUP210, BAZIA, FLJ10534, MARCH5, SEC1OL1, HNRPD, BRIPI, KLHL24, ETNK1, STAT1, SGPP1, CLCA4, FOXMl HNRPD, WARS, SFRS2, EPAS1, STATIC, EJIF4E, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, DCK, ARF6, CDC40, CXCL9, CXCL1O, FAS, PLK4, TRIM25, KITLG, 328 SLC25A11, C1QBP, NDUFA9, KPNB1, WHSC1, 88% 83% 85% 79% 81% 76% C17or125, CA2, ME2, TLK1, CXCL11, SLC4A4, RBM25, AK2, hCAP-D3, BAZ1A, AGPAT5, SEC1OL1, FLJ13220, PBK, KLHL24, ETNK1, MCAM, BUB3, YTHDC2, APOL6, NUP210 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, USP4, TES, LMAN1, ARF6, CDC40, CXCL9, IRF8, GTSE1, RABIF, CXCL1O, FAS, HNRPA3P1, C1QBP, NDUFA9, KPNB1, 329 SLC25A11, WHSC1, C17orf25, CA2, HNRPD, 88% 86% 85% 76% 77% 72% ME2, CXCL11, GZMB, SLC4A4, RBM25, AK2, SOCS6, CDC42BPA, RBBP4, AGPAT5, MARCH5, SEC1OL1, PSAT1, BRIPI, KLHL24, ETNK1, STATIC, CACNB3, BUB1B, ESPLI, H2AFZ WARS, SFRS2, EPAS1, EIF4E, MTHIFD2, PSME2, TK1, GMFB, DLGAP4, USP4, CXCL9, CXCL10, NDUFA9, KPNB1, SLC25A11, 330 C17orf25, ME2, CXCL11, RBBP4, hCAP-D3, 77% 79% 73% 79% 65% 69% ATP5A1, FAS, AGPAT5, FLJ10534, PBK, PSAT1, HNRPD, BRIP1, ETNK1, STATIC, LHCGR WARS, EIF4E, MTHFD2, PSME2, GBP1, DLGAP4, TYMS, CTSS, CDC40, SLC4A4, IRF8, 331 CXCL1O, FAS, TRI425, SLC25A11, ClQBP, 69% 72% 73% 86% 81% 76% NDUFA9, ME2, FUT4, RBBP4, TLK1, RBM25, AK2, FLJ10534, MARCH5, FLJ13220, ETNK1, STATIC, C18orf9, ClOorf3, AURKB, IFI16, PTPRC HNRPD, WARS, PAICS, EIF4E, PRDX3, MTHFD2, TK1, GMFB, TYMS, CTSS, CXCL9, FAS, KITLG, NDUFA9, SLC25A11, C17orf25, 332 ME2, FUT4, CXCL1 1, IFT20, SLC4A4, RBM25, 77% 83% 88% 76% 77% 72% CDC42BPA, SFRS2, AGPAT5, MARCH5, SEC1OL1, FLJ13220, PBK, PSAT1, BRIP1, KLHL24, STATIC, AK2 WARS, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, CXCL9, CXCL10, FAS, PLK4, 333 HNRPA3P1, TRIM25, SLC25A11, WHSC1, M2, 88% 86% 85% 66% 65% 79% CXCL1 1, IFT20, SLC4A4, RBM25, BAZ1A, AGPAT5, DKFZp762E1312, SEClOL1, PBK, HNRPD, BRIPI, ETNKI, STAT1, TOP2A, NUSAP1, USP14, PRF1, SCYL2 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CXCL10, FAS, WHSC1, C17orf25, ME2, IFT20, 88% 93% 88% 86% 73% 83% TLK1, CXCL1 1, SLC4A4, RBM25, AK2, CDC42BPA, HNRPD, ETNK1, STATIC, HLA DRA, POLE2, PAICS, NUP210 115 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN HNRPD, WARS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, CDC40, CXCL9, PLK4, 335 SLC25A11, WHSC1, Cl7orf25, CA2,ME2, IFT20, 81% 83% 92% 79% 88% 83% CXCL1 1, RBM25, hCAP-D3, FAS, FLJ10534, DKFZp762E1312, SEC1OL1, ETNK1, STAT1, WDHD1 WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, USP4, CTSS, MAD2L1, CXCL9, IRF8, GTSE1, CXCL1O, FAS, CHEKI, 336 KITLG, SLC25A11, C1QBP, NDUFA9, WHSC1, 77% 86% 85% 76% 81% 76% C17orf25, CA2, ME2, CXCL11, GZMB, IFT20, TLK1, SLC4A4, RBM25, hCAP-D3, BAZIA, MARCH5, DKFZp762E1312, SEC1OL1, FLJ13220, PSATI, HNRPD, BRIPI, KLHL24, ETNK1, STAT1, CUTL1, FAM64A WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CTSS, LMAN1, CDC40, CXCL9, IRF8, SLC25A11, 337 C1QBP, NDUFA9, CA2, ME2, FUT4, CXCL11, 77% 79% 92% 69% 92% 79% RBM25, AK2, CDC42BPA, FAS, RBBP4, AGPAT5, MARCH5, SEC1OL1, PBK, HNRPD, BRIPI, TRMT5, STAT1, TMEPAI, ZNF304, KLF7 WARS, SFRS2, EPASI, STAT 1, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, CDC40, SLC4A4, CXCL9, RABIF, CXCL1O, FAS, CHEKI, TRIM25, 338 SLC25A11, C1QBP, NDUFA9, WHSC1,CM, 81% 93% 92% 79% 81% 72% HNRPD, ME2, GZMB, RBBP4, CXCL11, RBM25, AK2, NUP210, BRRN1, ATP5A1, CDC42BPA, AGPAT5, FLJ10534, MARCH5, SEC10L1, FLJ13220, PBK, PSATI, BRIPI, MCM1O, HLA DMA, RABEP1, YARS, P15RS WARS, STATIC, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, MAD2L1, FAS, PLK4, TRIM25, 339 KITLG, SLC25A11, KPNB1, WHSC1, ME2, 73% 79% 77% 79% 69% 83% CXCL1 1, SLC4A4, RBM25, AK2, AGPAT5, KLHL24, CDKN1C, RFC5, FENI, TFRC WARS, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, DCK, CDC40, CXCL9, IRF8, GTSE1, CXCL1O, FAS, PLK4, TRIM25, SLC25A1 1, C1QBP, NDUFA9, 340 C17orf25, CA2, ME2, FUT4, CXCL11, SLC4A4, 73% 79% 85% 83% 81% 72% RBM25, AK2, CDC42BPA, RBBP4, BAZIA, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, PSATI, HNRPD, KLHL24, ETNK1, STAT1, SPFHI1, SP3, CDC20, RAP1GDS1, M11Si WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, ARF6, SLC4A4, CXCL9, CXCL1O, FAS, TRIM25, KITLG, CIQBP, NDUFA9, SLC25A11, 341 WHSC1, C17orf25, HNRPD, ME2, GZMB, TLK1, 96% 90% 81% 72% 73% 72% CXCL1 1, RBM25, AK2, BRRN1, DDAH2, AGPAT5, FLJ10534, SEC10L1, FLJ13220, PBK, PSATI, TRMT5, KLHL24, ETNK1, STAT1, AVEN, HLA-DPA1, CD59 116 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN WARS, SFRS2, EPASI, PRDX3, MTHFD2, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, SLC4A4, GTSE1, CXCL10, FAS, TRIM25, C1QBP, 342 NDUFA9, SLC25A1 1, WHSC1, C17orf25, CA2, 81% 83% 92% 79% 85% 79% HNRPD, ME2, FUT4, CXCL 11, RBM25, CDC42BPA, RBBP4, BAZ1A, AGPAT5, MARCH5, SEC10L1, BRIPI, TRMT5, KLHL24, STAT1, MPP5, EIF4A1, TRIP13, APOL3 WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, CDC40, CXCL9, CXCL10, FAS, CHEK1, 343 HNRPA3P1, SLC25A11, C1QBP, WHSC1, CA2 69% 79% 85% 83% 88% 76% HNRPD, ME2, CXCL1 1, TLK1, SLC4A4, RBM25, AK2, ATP5A1, SOCS6, BAZIA, AGPAT5, MARCH5, DKFZp762E1312, SEC10L, PBK, BRIPI, KLHL24, STATIC, GPR161, SGCD WARS, SFRS2, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, USP4, MAD2L1, CDC4O, SLC4A4, CXCL1O, FAS, CHEK1, KITLG, 344 NDUFA9, KPNB1, SLC25A1 1, CA2, HNRPD, 77% 86% 92% 79% 88% 86% ME2, FUT4, GZMB, CXCL1 1, RBM25, BRRN1, CDC42BPA, MARCH5, KLHL24, ETNK1, STATIC, ADHIC, WHSC1, HIP2 WARS, SFRS2, EPASI, PAICS, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, DCK, ARF6, SLC4A4, CXCL9, RABIF, CXCL10, FAS, TRIM25, SLC25A11, 345 C1QBP, NDUFA9, WHSC1, C17orf25, CA2, 81% 86% 88% 83% 88% 72% HNRPD, ME2, FUT4, GZMB, IFT20, CXCL11, RBM25, AK2, CAMSAP1L1, BRRN1, DDAH2, RBBP4, AGPAT5, PBK, PSAT1, BRIP1, KLHL24, STATIC, XPO7, TRAFD1, YTHDC2, RNF138 WARS, SFRS2, EPAS1, PRDX3, MTHFD2, PSME2, MCM6, DLGAP4, TYMS, USP4, CDC40, SLC4A4, CXCL9, RABIF, CXCL10, FAS, 346 SLC25A11, C1QBP, NDUFA9, WHSC1, CA2 81% 83% 85% 76% 81% 72% ME2, CXCL11, RBM25, NUP210, BRRN1, DDAH2, RBBP4, BAZ1A, DKFZp762E1312, SEC10L1, PSAT1, HNRPD, KLHL24, ETNK1, STATIC, ACADSB, AMIGO2, CCL5, KIAA0286 SFRS2, EPASI, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, DCK, ARF6, CDC40, CXCL9, GTSE1, CXCL1O, FAS, 347 SLC25A11, KPNB1, WHSC1, CA2, HNRPD, ME2, CXCL11, SLC4A4, RBM25, AK2, ATP5A1, 81% 83% 92% 79% 85% 79% CDC42BPA, BAZIA, FLJ10534, FLJ13220, PBK, BRIP1, KLHL24, STAT1, PSMB9, HBP1, CPD, AIM2 WARS, EPAS1, EIF4E, PRDX3, MTHFD2, MCM6, GMFB, DLGAP4, CDC40, CXCLIO, 348 CHEK1, KPNB1, CA2, ME2, RBBP4, CXCL11 SLC4A4, RBM25, CDC42BPA, FAS, FLJ10534, 73% 86% 73% 86% 73% 79% SEC1OL1, FLJ13220, HNRPD, STATIC, TTK, YBX2, BCL7C, SI WARS, SFRS2, STAT1, EIF4E, PRDX3, 349 MTHFD2, TK1, GMFB, DLGAP4, TYMS, USP4, 88% 79% 96% 69% 88% 76% TES, CTSS, CXCL9, CXCL10, FAS, SLC25A1 1, 117 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN KPNB1, C17orf25, ME2, GZMB, SLC4A4, NUP2 10, hCAP-D3, HNRPD, TRMT5, KLHL24, PR02730 EPAS1, EIF4E, PRDX3, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, SLC4A4, CXCL1O, HNRPA3P1, KITLG, SLC25A11, 350 WHSC1, CA2, HNRPD, ME2, FUT4, RBM25 73% 83% 92% 79% 81% 76% CAMSAP1L1, FAS, AGPAT5, FLJ10534, MARCH, SEC1OL1, PSATI, BRIP1, KLIIL24, STAT1, MCM2, GGA2, SPAG5, VRK1, EBNA1BP2 WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, LMAN1, MAD2L1, SLC4A4, CXCL9, RABIF, CXCL10, FAS, 351 CHEK1, KITLG, SLC25A11, NDUFA9, C17orf25, 85% 76% 88% 83% 88% 76% CA2, ME2, IFT20, CXCL11, RBM25, hCAP-D3, CDC42BPA, AGPAT5, MARCH, HNRPD, KLHL24, STATIC, MYCBP, GBP1, ITGA4, PBXIP1, CENPA HNRPD, WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CTSS, ARF6, CDC40, SLC4A4, CXCL9, CXCL10, FAS, TRIM25, KITLG, NDUFA9, SLC25A1 1, 352 C17orD25, CA2, ME2, FUT4, GZMB, CXCL11, 77% 79% 92% 76% 77% 76% BRRN1, SOCS6, CDC42BPA, BAZIA, DKFZp762E1312, SEC10L1, PBK, PSATI, BRIPI, TRMT5, ETNK1, STATIC, PPIG, NUP98, FUSIP1, SH3GLB1 WARS, SFRS2, EPASI, EIF4E, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, DCK, CDC40, CXCL9, GTSE1, RABIF, CXCL1O, KITLG, C1QBP, NDUFA9, SLC25A11, C17orf25, 85% 83% 88% 79% 73% 72% CA2, ME2, GZMB, IFT20, SLC4A4, RBM25, DDAH2, FAS, AGPAT5, FLJ10534, MARCH, FLJ13220, PBK, HNRPD, KLHL24, ETNK1, STATIC, C5orf4, KIF23, SSPN HNRPD, WARS, SFRS2, STAT 1, EIF4E, SFPQ, PSME2, GBP1, GMFB, DLGAP4, TYMS, CTSS, ARF6, CDC40, SLC4A4, CXCL10, FAS, C1QBP, 354 NDUFA9, SLC25A11, WHSCI, CA2, ME2, IFT20, 85% 83% 92% 83% 81% 76% RBBP4, CXCL11, RBM25, NUP210, BAZIA, AGPAT5, MARCH, PBK, KLHL24, MAP2K4, UBE2L6 HNRPD, WARS, EIF4E, MTHFD2, MCM6, DLGAP4, TYMS, CDC40, CXCL9, CXCL10, FAS, 355 TRIM25, C1QBP, ME2, CXCL11, RBM25, AK2, 88% 90% 73% 79% 73% 76% CDC42BPA, SEC1OL1, PBK, KLHL24, ETNK1, STATIC, DNA2L, TAP2, SYNPO HNRPD, WARS, EIF4E, MTHFD2, GBPI, GMFB, DLGAP4, TYMS, USP4, DCK, CDC40, CXCL9, IRF8, GTSE1, CXCL1O, HNRPA3P1, TRIM25, C1QBP, NDUFA9, SLC25A1 1, WHSCI, 356 CA2, ME2, FUT4, CXCL11, RBBP4, TLK1, 69% 83% 85% 83% 81% 79% SLC4A4, RBM25, AK2, NUP210, ATP5AI, SFRS2, FAS, AGPAT5, FLJ10534, MARCH, SEClOL1, PBK, KLHL24, ETNK1, STAT1, EXOSC9, KIF15, FBXL14, ABCE1 118 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, LMAN1, CDC40, SLC4A4, CXCL9, IRF8, CXCL10, FAS, PLK4, HNRPA3P1, C1QBP, 357 NDUFA9, SLC25A11, WHSC1, C17orf25, CA2, 85% 86% 88% 79% 81% 72% HNRPD, ME2, CXCL11, RBM25, AK2, CDC42BPA, RBBP4, AGPAT5, FLJ10534, SEC1OL1, FLJ13220, PBK, BRIP1, STAT1, CCL5, FLJ20516, BUBI, MRPL42 HNRPD, WARS, EIF4E, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, ARF6, MAD2L1, CDC40, SLC4A4, CXCL9, CXCL10, 358 FAS, PLK4, C1QBP, SLC25AI1, WHSC1, CA2, 77% 83% 85% 79% 81% 69% ME2, CXCL1 1, RBBP4, RBM25, AK2, CDC42BPA, BAZ1A, AGPAT5, SEC1OLL, PBK, PSAT1, BRIPI, ETNK1, STATIC, GZMA, EIF4A1, PSMA3, CD2,.CCNB1 WARS, PSME2, GMFB, DLGAP4, TYMS, CDC40, CXCL9, GTSEl, CXCL1O, FAS, TRIM25, 359 SLC25A11, C1QBP, NDUFA9, WHSC1, C17orf25, 7 79% 81% 76% 77% 66% ME2, CXCL11, RBM25, CAMSAP1L1, AGPAT5, FLJ13220, PSATI, TRMT5, KLHL24, ETNK1, STAT1, RRM1, CXCL13, NKG7, MGAT2, LCP2 HNRPD, SFRS2, EPAS1, STAT1, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CXCL9, CXCL10, FAS, CHEKI, 360 HNRPA3P1, KPNB1, SLC25A11, WHSC1, C17orf25, ME2, CXCL11, IFT20, TLK1, SLC4A4, 88% 90% 85% 79% 73% 76% RBM25, CDC42BPA, BAZIA, AGPAT5, MARCH5, SEClOL1, PBK, PSATI, KLHL24, ClorfIl 12, TCF7L2, RARRES3, SERBP1, TBX2 HNRPD, WARS, EIF4E, SFPQ, MTHFD2, PSME2, GMIFB, DLGAP4, TYMS, TES, CTSS, ARF6, CXCL9, IRF8, RABIF, CXCL10, FAS, PLK4, HNRPA3P1, KITLG, SLC25A11, C1QBP, 361 NDUFA9, WHSC1, C17orf25, ME2, CXCL11, 81% 83% 88% 76% 77% 69% IFT20, TLK1, RBM25, AK2, NUP210, hCAP-D3, CDC42BPA, DDAH2, AGPAT5, FLJ10534, SEC1OL1, PBK, KLHL24, STAT1, PTGER3, HCAP-G HNRPD, WARS, SFRS2, EPASI, STATIC, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, CTSS, LMAN1, MAD2L1, 362 CDC40, CXCL9, IRF8, CXCL1O, KITLG, C1QBP, 81% 90% 85% 79% 77% 83% NDUFA9, SLC25A11, WHSC1, ME2, CXCL11, GZMB, IFT20, RBBP4, SLC4A4, RBM25, hCAP D3, BRRN1, FAS, FLJ10534, SEC1OL1, PSATI, KLHL24, NUP50, MCCC2, RABGEF1 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, GMFB, DLGAP4, TYMS, USP4, CDC40, CXCL9, CXCL10, FAS, HNRPA3P1, TRIM25, ClQBP, 363 SLC25A11, ME2, CXCL11, IFT20, RBM25, AK2, 92% 90% 77% 83% 69% 72% hCAP-D3, CDC42BPA, RBBP4, BAZ1A, DKFZp762E1312, SEC1OL1, PBK, HNRPD, ETNK1, STATIC, PSMA6, ZNF345, UBAPI 364 WARS, EPASI, PAICS, EIF4E, MTHFD2, PSME2, GMFB, TYMS, TES, LMAN1, SLC4A4, 77% 86% 88% 76% 85% 76% 119 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN INN CXCL9, RABIF, FAS, CHEK1, HNRPA3P1, TRIM25, SLC25A11, C1QBP, WHSC1, ME2, CDC42BPA, FLJ10534, SEClOL1, PBK, STATIC, ZBTB20, NAT2 WARS, SFRS2, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, MAD2L1, CXCL9, CXCL10, FAS, ClQBP, NDUFA9, 365 KPNB1, SLC25A11, WHSC1, CA2, ME2, IFT20, 85% 86% 85% 76% 81% 69% SLC4A4, RBM25, AK2, CDC42BPA, DDAH2, PSAT1, HNRPD, BRIPI, KLHL24, ETNK1, STAT1, HMMR, CTSL WARS, EIF4E, PRDX3, MTHFD2, PSME2, GMIFB, DLGAP4, TYMS, USP4, CTSS, DCK, CXCL9, CXCL10, FAS, TRIM25, WHSC1, 366 ClI7orf25, CA2, ME2, FUT4, IFT20, CXCLl1, 88% 83% 85% 72% 69% 76% SLC4A4, RBM25, CDC42BPA, RBBP4, AGPAT5, MARCH5, FLJ13220, PBK, HNRPD, TRMT5, KLHL24, ETNK1, STAT1, PBX1, ZDHHC3, CLEC2D HNRPD, WARS, SFRS2, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, LMAN1, ARF6, CDC40, CXCL9, IRF8, GTSE1, RABIF, CXCL10, FAS, KITLG, C1QBP, 367 NDUFA9, SLC25A11, WHSC1, ME2, TLK1, 73% 83% 85% 83% 73% 66% SLC4A4, CXCL1 1, RBM25, hCAP-D3, DDAH2, RBBP4, BAZIA, AGPAT5, SEC1OL1, PBK, TRMT5, KLHL24, ETNK1, STAT1, NEK2, KIAA0841, RNMT, C4orfl6 WARS, SFRS2, EPAS1, STATIC, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, CDC40, SLC4A4, CXCL9, RABIF, CXCL10, FAS, PLK4, CHEKI, HNRPA3P1, TRIM25, ClQBP, KPNB1, 368 SLC25A11, WHSC1, CA2, HNRPD, ME2, FUT4, 73% 83% 81% 79% 81% 72% RBBP4, CXCL11, RBM25, NUP210, SOCS6, CDC42BPA, FLJ10534, MARCH5, FLJ13220, PBK, PSATI, BRIP1, KLHL24, APOL1, PDGFA, FBXO5, CACYBP, ABCE1 WARS, SFRS2, EPASI, STATIC, PAICS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, DCK, CDC40, SLC4A4, CXCL9, GTSE1, CXCL1O, PLK4, SLC25A11, NDUFA9, KPNB1, 369 WHSC1, C17orf25, CA2, ME2, FUT4, IFT20, 88% 86% 81% 83% 81% 79% TLK1, CXCL1 1, RBM25, AK2, CDC42BPA, DDAH2, FAS, BAZIA, AGPAT5, SEC1OL1, FLJ13220, PBK, PSATI, HNRPD, BRIPI, BMP5, ETNK1, PTGER3, VAMP4, CCNB2 WARS, EPAS1, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, CTSS, MAD2L1, CDC40, SLC4A4, CXCL9, GTSE1, RABIF, CXCL10, FAS, PLK4, TRIM25, KITLG, 370 SLC25A11,C1QBP,CA2,ME2,CXCL11,RBBP4, 81% 79% 81% 79% 81% 76% TLK1, RBM25, AK2, BRRN1, SFRS2, BAZIA, AGPAT5, FLJ13220, PSAT1, HNRPD, BRIP1, KLHL24, STATIC, TAP1, LCP2, ITGAL, CCNT2, FYB 371 HNRPD, WARS, PRDX3, MTHFD2, PSME2, 88% 79% 85% 79% 73% 72% MCM6, TK1, GMFB, DLGAP4, TYMS, DCK, 88_9_8% 7%_3_2 120 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN ARF6, CXCL9, CXCL1O, C1QBP, NDUFA9, SLC25A1 1, ME2, IFT2O, CXCL1 1, RBM25, AK2, BRRN1, ATP5A1, CDC42BPA, SFRS2, FAS, BAZ1A, AGPAT5, FLJ13220, PBK, PSAT1, BRIP1, KLHL24, STATIC, NEIL3, PCDHGC3, NUSAPI SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, TES, DCK, MAD2L1, CXCL9, IRF8, CXCL10, FAS, TRIM25, KITLG, C1QBP, NDUFA9, 372 SLC25A11, WHSC1, CA2, HNRPD, ME2, 77% 79% 81% 83% 85% 79% CXCL1 1, IFT20, RBBP4, SLC4A4, RBM25, AK2, CDC42BPA, DDAH2, BAZIA, AGPAT5, FLJ10534, MARCH5, SEC10L1, FLJ13220, PBK, KLHL24, ETNK1, STATIC, TNFAIP2 WARS, STATIC, EIF4E, SFPQ, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, ARF6, CDC40, SLC4A4, CXCL9, RABIF, CXCL1O, FAS, 373 SLC25A11, C1QBP, NDUFA9, KPNB1, WHSC1, 85% 86% 92% 79% 81% 72% C17orf25, CA2, ME2, FUT4, CXCL1 1, GZMB, TLK1, RBM25, AK2, FLJ10534, FLJ13220, HNRPD, BRIPI, GEMIN4, PTPRC WARS, SFRS2, EPASI, PAICS, EIF4E, MTHFD2, PSME2, MCM6, GBP1, GMFB, DLGAP4, TYMS, TES, CTSS, DCK, MAD2L1, CDC40, SLC4A4, CXCL9, IRF8, GTSE1, CXCL1O, FAS, PLK4, TRIM25, KITLG, C1QBP, 374 NDUFA9, KPNB1, SLC25A11, WHSC1, CA2, 77% 90% 81% 76% 85% 76% ME2, CXCL11, RBM25, AK2, hCAP-D3, CDC42BPA, DDAH2, AGPAT5, MARCH5, SEC10L1, FLJ13220, PBK, HNRPD, BRIP1, KLHL24, STATIC, APOBEC3G, KIF 1, GBP2, RAB6A, ITGB5 WARS, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, MAD2L1, CDC40, CXCL9, CXCL10, FAS, SLC25Al1, ClQBP, 375 NDUFA9, ME2, FUT4, CXCL11, RBM25, hCAP- 73% 72% 85% 90% 81% 83% D3, BRRN1, MARCH5, SEC1OL1, FLJ13220, HNRPD, STAT1, AP2B1, KIF2, K-ALPHA-1, GPHN HNRPD, WARS, SFRS2, EPASI, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, CXCL9, IRF8, RABIF, CXCL10, FAS, HNRPA3P1, 376 KITLG, SLC25A11, C1QBP, NDUFA9, WHSC1, 77% 83% 77% 86% 73% 86% ME2, CXCL1 1, TLK1, SLC4A4, RBM25, ATP5AI, RBBP4, FLJ10534, MARCH5, FLJ13220, PSATI, BRIP1, KLHL24, STATIC, KIIF18A, KIF2C, NF2, DLG7, PSMAS WARS, SFRS2, EPASI, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CDC40, CXCL9, CXCL10, FAS, PLK4, TRIM25, KITLG, 377 C1QBP, NDUFA9, SLC25A1 1, HNRPD, ME2, 81% 90% 85% 90% 88% 72% CXCL11, IFT20, RBM25, ATP5A1, DDAH2, AGPAT5, FLJ13220, PSATI, BRIP1, KLHL24, STATIC, SLC4A4, CD7, DNMIL, RPL39, CDKN3 378 HNRPD, WARS, SFRS2, EPASI, STATI, EIF4E, 85% 90% 85% 72% 73% 79% 121 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN PRDX3, MTHFD2, PSME2, TK1, DLGAP4, TYMS, USP4, LMAN1, DCK, MAD2L1, CDC40, SLC4A4, CXCL9, GTSE1, RABIF, CXCL1O, FAS, PLK4, CHEKI, HNRPA3P1, TRIM25, ClQBP, NDUFA9, SLC25A11, WHSC1, ME2, CXCL11, GZMB, IFT20, RBBP4, TLK1, RBM25, AK2, ATP5A1, AGPAT5, KLHL24, ETNK1, CD3Z, DHX15, MTHFD1 WARS, STAT1, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, DCK, SLC4A4, CXCL9, IRF8, RABIF, CXCL10, FAS, TRIM25, NDUFA9, SLC25A1 1, WHSC1, HNRPD ME2, CXCL11, TLK1, RBM25, CAMSAP1L1, ' 81% 83% 77% 83% 77% 79% CDC42BPA, RBBP4, MARCH5, SEC10L1, FLJ13220, PSATI, BRIPI, KLHL24, ETNK1, ATF6, RRM2, KPNA2 HNRPD, WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GBPI, TKi, DLGAP4, TYMS, LMAN1, MAD2L1, CXCL9, IRF8, CXCL1O, FAS, 30 NRPA3P1, KITLG, NDUFA9, KPNB1, 380 SLC25A11, ME2, CXCL11, TLK1, SLC4A4, 73% 83% 81% 86% 69% 72% RBM25, AK2, AGPAT5, FLJ10534, MARCH5, SEC1OL1, PBK, PSATI, BRIPI, KLHL24, STAT1, BTN3A3 WARS, EIF4E, PRDX3, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, TES, CDC40, CXCL9, CXCL10, FAS, KITLG, NDUFA9, 381 SLC25A11, WHSC1, CA2, ME2, RBM25, AK2, 85% 83% 92% 86% 85% 76% ATP5A1, SEC1OL1, PBK, HNRPD, BRIP1, KLHL24, STAT1, CHEKI, C20orf45, CKS2 WARS, SFRS2, EPAS1, EIF4E, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, ARF6, MAD2L1, CXCL9, RABIF, CXCL1O, FAS, 382 PLK4, CHEK1, HNRPA3P1, KITLG, SLC25AI1, 92% 90% 81% 79% 73% 76% WHSC1, C17orf25, ME2, FUT4, CXCL11, IFT20, SLC4A4, RBM25, ATP5A1, CDC42BPA, RBBP4, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, ETNK1, STAT1, HMGN2, SFRS1O . WARS, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, GMFB, DLGAP4, TYMS, USP4, DCK, CDC40, CXCL9, IRF8, RABIF, CXCL10, 383 FAS, PLK4, HNRPA3P1, TRIM25, KITLG, C1QBP, NDUFA9, SLC25A1 1, C17orf25, CA2, 85% 83% 88% 76% 81% 72% HNRPD, ME2, CXCL1 1, RBM25, SFRS2, DDAH2, RBBP4, AGPAT5, FLJ13220, PBK, ETNK1, STATIC, TMEM48 WARS, SFRS2, EPAS1, EIF4E, SFPQ, GMFB, DLGAP4, TYMS, USP4, SLC4A4, CXCL9, 384 RABIF, CXCL10, FAS, KPNB1, CA2, ME2, 88% 90% 88% 83% 81% 76% FUT4, CXCL1 1, RBM25, CAMSAP1L1, KLHL24, STATIC, TRAF3IP3, SOSI WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, USP4, MAD2L1, 385 SLC4A4, CXCL9, GTSE1, RABIF, CXCL1O, FAS, 85% 86% 88% 79% 73% 79% HNRPA3P1, TRIM25, SLC25A1 1, NDUFA9, WHSC1, CA2, ME2, GZMB, TLK1, CXCL11, RBM25, AK2, BRRN1, ATP5A1, DDAH2, 122 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN AGPAT5, MARCH5, SEC1OL1, PBK, PSATI, HNRPD, BRIPI, KLHL24, STAT1, C16orf3O WARS, SFRS2, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, LMAN1, CXCL9, IRF8, GTSE1, CXCL1O, FAS, TRIM25, KITLG, SLC25A1 1, 386 C1QBP,NDUFA9,KPNB1,WHSC1,HNRPD, 69% 76% 69% 86% 81% 86% ME2, CXCL11, IFT20, RBBP4, TLK1, SLC4A4, RBM25, CAMSAP1L1, ATP5A1, DDAH2, FLJ10534, MARCH5, DKFZp762E1312, SEC10L1, PBK, TRMT5, STAT1, PGD, ZNF148 HNRPD, WARS, EPASI, PRDX3, MTHFD2, PSME2, TK1, DLGAP4, TYMS, USP4, TES, 387 LMAN1, CXCL9, CXCL1O, FAS, PLK4, TRIM25, 73% 86% 88% 83% 81% 83% C1QBP, SLC25A1 1, WHSC1, ME2, RBBP4, TLK1, SLC4A4, NUP210, SFRS2, SEC1OL1, ETNK1, STATIC, SNRPC, RAC2 WARS, SFRS2, PAICS, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, TES, LMAN1, 388 CDC40, CXCL1O, NDUFA9, KPNB1, SLC25A11, 7 79% 73% 86% 77% 83% ME2, CXCL11, SLC4A4, RBM25, NUP210, hCAP-D3, FAS, RBBP4, ETNK1, STATIC, DHX40, KIA0090 HNRPD, WARS, SFRS2, EPAS1, STATIC, EIF4E, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, LMAN1, ARF6, CXCL1O, FAS, PLK4, TRIM25, 389 SLC25AI1, C1QBP, NDUFA9, ME2, CXCL11, 85% 86% 88% 76% 81% 83% GZMB, TLKI, SLC4A4, RBM25, hCAP-D3, ATP5A1, CDC42BPA, DDAH2, AGPAT5, FLJ10534, MARCH5, FLJ13220, SLA WARS, EPASI, EIF4E, PRDX3, TK1, GMFB, DLGAP4, USP4, CXCL9, CXCL10, FAS, CHEKI, 390 KITLG, C1QBP, NDUFA9, SLC25A11, WHSC1, 88% 86% 81% 83% 81% 86% ME2, IFT20, RBM25, HNRPD, BRIP1, ETNK1, STATIC, MASA, SYDE1, C9orf76, ZNF518 WARS, SFRS2, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, CXCL9, RABIF, CXCL1O, 391 HNRPA3P1, TRIM25, KITLG, SLC25A11, ME2, 85% 79% 92% 79% 88% 76% RBBP4, CXCL11, RBM25, SOCS6, FAS, AGPAT5, MARCH5, SEC1OL1, HNRPD, BRIPI, STAT1, KIAA0265, CCNA2, LRP8, CNAPI HNRPD, WARS, SFRS2, EIF4E, PRDX3, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, USP4, CTSS, ARF6, CXCL9, IRF8, GTSEl, CXCL1O, TRIM25, C1QBP, SLC25A11, WHSC1, 392 CA2, ME2, FUT4, CXCL1 1, GZMB, SLC4A4, 85% 90% 88% 79% 85% 69% RBM25, AK2, CAMSAP1L1, ATP5A1, SOCS6, CDC42BPA, FAS, RBBP4, BAZIA, AGPAT5, MARCH5, SEC1OL1, PBK, BRIP1, KLHL24, STATIC, GTPBP3, MOBK1B, MDS032, WDR45L HNRPD, WARS, SFRS2, STATIC, EIF4E, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, TES, DCK, CDC40, CXCL9, IRF8, 393 CXCL1O, FAS, PLK4, SLC25A1 1, C1QBP, 81% 79% 77% 86% 69% 66% NDUFA9, KPNB1, C17orf25, ME2, IFT20, RBBP4, TLK1, SLC4A4, CXCL1 1, RBM25, AK2, NUP210, ATP5A1, CDC42BPA, SEC1OL1, 123 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN FLJ13220, PBK, PSATI, BRIPI, KLHL24, ETNK1, FLJ20641, PIK3CD WARS, SFRS2, EIF4E, PRDX3, MTBFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, MAD2L1, CDC40, CXCL9, IRF8, CXCLO, 81% 90% 85% 79% 85% 72% WHSC1, C17orf25, CA2, HNRPD, ME2, CXCL11, GZMB, SLC4A4, RBM25, AK2, FAS, SEC1OL1, KLHL24, STATIC, KIAA0907 WARS, SFRS2, EPAS1, PAICS, EIF4E, PRDX3, MTHFD2, PSME2, DLGAP4, TYMS, TES, DCK, CDC40, SLC4A4, IRF8, CXCL10, PLK4, C1QBP, 395 NDUFA9, SLC25A11, WHSC1, CA2, ME2, FUT4, 85% 86% 85% 72% 69% 76% GZMB, TLK1, CXCL1 1, RBM25, hCAP-D3, FAS, AGPAT5, MARCH5, SEC10L1, PSATI, HNRPD, BRIP1, STATIC, NUMB, HMGB2 WARS, EIF4E, MTHFD2, GMFB, DLGAP4, CTSS, CDC40, CXCL1O, FAS, HNRPA3P1, 396 C1QBP, NDUFA9, SLC25A1 1, HNRPD, ME2, 81% 83% 81% 90% 73% 79% FUT4, CXCL1 1, RBM25, ATP5A1, FLJ10534, SEC1OL1, FLJ13220, PBK, BRIP1, STAT1, KPNA2, IBRDC3, RIG, NP WARS, EPASI, EIF4E, MTHFD2, PSME2, TK1, GMFB, DLGAP4, TYMS, USP4, LMAN1, DCK, CDC40, CXCL9, IRF8, GTSEl, CXCL1O, FAS, TRIM25, KITLG, SLC25A1 1, ClQBP, NDUFA9, KPNB1, WHSC1, C17orf25, CA2, HNRPD, ME2, 81% 83% 92% 76% 73% 76% CXCL1 1, GZMB, RBM25, AK2, NUP210, ATP5A1, DDAH2, FLJ10534, MARCH5, FLJ13220, PBK, PSATI, BRIP1, TRMT5, KLHL24, ETNK1, STAT1, SFRS7, SMURF2, SCC-1 12 WARS, SFRS2, PRDX3, PSME2, TK1, GMFB, DLGAP4, TYMS, TES, MAD2L1, CXCL9, GTSE1, CXCL1O, PLK4, TRIM25, C1QBP, 398 NDUFA9, KPNB1, WHSC1, C17orf25, CA2, ME2 92% 97% 88% 76% 81% 79% CXCL1 1, GZMB, IFT20, SLC4A4, RBM25, AK2, hCAP-D3, ATP5A1, FAS, MARCH5, PBK, HNRPD, ETNK1, STATIC, HEM1, DKK1, PRDX1, ELOVL6, CD86 HNRPD, WARS, SFRS2, EPAS1, EIF4E, PRDX3, MTHFD2, PSME2, MCM6, GMFB, DLGAP4, TYMS, USP4, LMAN1, CDC40, SLC4A4, CXCL9, GTSEl, CXCL1O, FAS, PLK4, SLC25A1 1, 399 C1QBP, NDUFA9, KPNB1, WHSC1, C17orf25, 85% 79% 88% 79% 88% 76% CA2, ME2, CXCL1 1, IFT20, RBM25, BRRN1, CDC42BPA, RBBP4, AGPAT5, MARCH5, SEC1OL1, PBK, TRMT5, KLHL24, STATIC, PEG3, ASPM, NR5A2 WARS, SFRS2, PAICS, EIF4E, SFPQ, PRDX3, MTHFD2, PSME2, GMFB, DLGAP4, TYMS, USP4, CTSS, LMAN1, DCK, MAD2L1, CXCL9, IRF8, CXCL10, PLK4, KITLG, C1QBP, NDUFA9, 400 KPNB1, SLC25A11, WHSC1, C17orf25, CA2, 65% 79% 92% 86% 85% 76% HNRPD, ME2, CXCL11, TLK1, SLC4A4, RBM25, AK2, ATP5A1, FAS, RBBP4, BAZIA, FLJ10534, SEClOL1, FLJ13220, PBK, PSAT1, BRIPI, KLHL24, STAT1, AMD1 124 WO 2007/073220 PCT/NZ2006/000343 SVM 3NN 1NN HNRPD, WARS, EIF4E, MTHFD2, PSME2, GBP1, TK1, GMFB, DLGAP4, TYMS, USP4, TES, MAD2L1, CXCL9, CXCL1O, FAS, TRIM25, NDUFA9, WHSC1, C17orf25, CA2, ME2, 401 CXCL11, TLK1, SLC4A4, RBM25, BRRN1, 85% 79% 85% 86% 81% 76% DDAH2, MARCH5, PBK, PSATI, BRIP1, KLHL24, STATI, LOC146909, ECT2, BM039, GTF3C4 WARS, EPASI, STAT1, EIF4E, MTHFD2, TK1, GMFB, DLGAP4, TYMS, USP4, CTSS, DCK, ARF6, CDC40, CXCL9, CXCL10, PLK4, HNRPA3P1, TRI425, KITLG, SLC25A11, 402 INDUFA9, WHSC1, C17orf25, CA2, HNRPD, 81% 79% 88% 79% 81% 79% ME2, CXCL11, IFT20, TLK1, SLC4A4, RBM25, AK2, CAMSAP1L1, ATP5A1, SOCS6, SFRS2, DDAH2, FAS, RBBP4, MARCH5, SEC1OL1, FLJ13220, PBK, PSATI, BRIPI, KLHL24, MS4A12, SMCHD1, RANBP2L1, SP110, SE57-1 WARS, SFRS2, EPASI, STATIC, EIF4E, MTHFD2, PSME2, MCM6, TK1, GMFB, DLGAP4, TYMS, TES, CDC40, SLC4A4, CXCL9, 403 IRF8, GTSE1, CXCL10, FAS, CHEKI, SLC25AI1, 73% 86% 81% 83% 69% 79% ClQBP, NDUFA9, WHSC1, C17orf25, CA2, ME2, FUT4, TLK1, RBM25, CAMSAP1L1, hCAP-D3, DDAH2, RBBP4, FLJ10534, PBK, PSATI, BRIPI, KLHL24, ETNK1, CAND1 Example 20: Specific Application of Prediction Methods 5 In selection of the gene signatures described here, two different statistical methods were used to characterise the signatures: k-nearest neighbours, and support vector machines. These methods are provided as packages to the R statistical software system (ref), through the packages class (ref) and e1071 (ref).. The signatures described in this document were tested as follows. In both cases, the 10 data used to develop the prediction models for a given signature were the gene expression values (raw normalised intensities from the Affymetrix array data) for the probes corresponding to genes that comprise that signature, across both recurrent and non-recurrent samples: * For k-nearest neighbours, we used leave-one-out cross validation with k=1 and 15 k=3 to obtain sensitivity (proportion of positive, i.e. recurrent, samples correctly classified) and specificity (proportion of negative samples, i.e. non recurrent samples correctly classified) described in table 9 125 WO 2007/073220 PCT/NZ2006/000343 e The dataset was used to generate leave-one-out cross-validation sensitivity and specificity data using the following support-vector machine parameters: The support vector machine models were generated using a linear kernel, and all other parameters used were the default values obtained from the svm function 5 of the e1071 package. Note the genes comprising the signatures were themselves obtained from the list of significantly differentially expressed probes, and those from the list of genes which were found to correlate with genes from the NZ 22-gene signature. In some cases there was more than one significant (or correlated) probe per gene. In these cases, the 10 prediction models used the median intensity data across all significant probes (i.e. those in the significant probe list, see table 1) for that gene. References 1. Arnold CN, Goel A, Blum HE, Richard Boland C. Molecular pathogenesis of 15 colorectal cancer. Cancer 2005;104:2035-47. 2. Anwar S, Frayling IM, Scott NA, Carlson GL. Systematic review of genetic influences on the prognosis of colorectal cancer. Br J Surg 2004;91:1275-91. 3. Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol 2004;22:1564 20 71. 4. Eschrich S, Yang I, Bloom G, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 2005;23:3526-35. 5. Barrier A, Lemoine A, Boelle PY, et al. Colon cancer prognosis prediction by gene expression profiling. Oncogene 2005;24:6155-64. 25 6. Simon R. Roadmap for developing and validating therapeutically relevant genomic classifiers. J Clin Oncol 2005;23:7332-41. 7. Michiels S, Koscielny S, Hill C. Prediction of cancer outcome with microarrays: a multiple random validation strategy. Lancet 2005;365:488-92. 8. Marshall E. Getting the noise out of gene arrays. Science 2004;306:630-31. 30 9. Birkenkamp-Demtroder K, Christensen LL, Olesen SH, et al. Gene expression in colorectal cancer. Cancer Res 2002;62:4352-63. 10. Ihaka R, Gentleman R. R: A language for data analysis and graphics. Journal of Computational and Graphical Statistics 1996;5:299-314. 126 WO 2007/073220 PCT/NZ2006/000343 11. Smyth GK. 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Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. Cancer Res 2002;62:1251-55. 17. Niki T, Izumi S, Saegusa Y, et al. MSSP promotes ras/myc cooperative cell transforming activity by binding to c-Myc. Genes Cells 2000;5:127-41. 20 18. Rein DT, Roehrig K, Schondorf T, et al. Expression of the hyaluronan receptor RHAMM in endometrial carcinomas suggests a role in tumor progression and metastasis. J Cancer Res Clin Oncol 2003;129:161-64. 19. Fernandez P, Carretero J, Medina PP, et al. Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations. Oncogene 2004;23:5084-91. 25 20. Frey UH, Eisenhardt A, Lummen G, et al. The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer. Cancer Epidemiol Biomarkers Prev 2005;14:871-77. 21. Niini T, Vettenranta K, Holhnen J, et al. Expression of myeloid-specific genes in childhood acute lymphoblastic leukemia - a cDNA array study. Leukemia 30 2002;16:2213-21. 22. Yasui K, Mihara S, Zhao C, et al. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res 2004;64:1403-10. 127 WO 2007/073220 PCT/NZ2006/000343 23. Nomura J, Matsumoto K, Iguchi-Ariga SM, Ariga H. Positive regulation of Fas gene expression by MSSP and abrogation of Fas-mediated apoptosis induction in MSSP-deficient mice. Exp Cell Res 2005;305:324-32. 24. Mayeur GL, Fraser CS, Peiretti F, Block KL, Hershey JW. Characterization of 5 eIF3k: a newly discovered subunit of mammalian translation initiation factor elF3. Eur J Biochem 2003;270:4133-39. 25. Hsieh YJ, Wang Z, Kovelman R, Roeder RG. Cloning and characterization of two evolutionarily conserved subunits (TFIIIC102 and TFIIIC63) of human TFIIIC and their involvement in functional interactions with TFIIIB and RNA polymerase III. 10 Mol Cell Biol 1999;19:4944-52. 26. Matsumoto S, Abe Y, Fujibuchi T, et al. Characterization of a MAPKK-like protein kinase TOPK. Biochem Biophys Res Commun 2004;325:997-1004. 27. Dong VM, McDermott DH, Abdi R. Chemokines and diseases. Eur J Dermatol 2003; 13:224-30. 15 28. Abe Y, Matsumoto S, Kito K, Ueda N. Cloning and expression of a novel MAPKK-like protein kinase, lymphokine-activated killer T-cell-originated protein kinase, specifically expressed in the testis and activated lymphoid cells. J Biol Chem 2000;275:21525-31. 29. Logan GJ, Smyth CM, Earl JW, et al. HeLa cells cocultured with peripheral 20 blood lymphocytes acquire an immuno-inhibitory phenotype through up-regulation of indoleamine 2,3-dioxygenase activity. Immunology 2002;105:478-87. 30. Lubeseder-Martellato C, Guenzi E, Jorg A, et al. Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases. Am J Pathol 25 2002;161:1749-59. 31. 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The relationship between tumor T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer 2005;92:65 1 54. 10 36. Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol 2000;18:217-42. 37. Miyazaki M, Nakatsura T, Yokomine K, et al. DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4 T cells and CD8 T cells. Cancer Sci 2005;96:695-705. 15 38. Ein-Dor L, Kela I, Getz G, Givol D, Domany E. Outcome signature genes in breast cancer: is there a unique set? Bioinformatics 2005;21:171-78. 39. Becker RA, Chambers, JM and Wilks AR The New S Language. Wadsworth & Brooks/Cole 1988. 40. Gentleman R., Carey VJ, Huber W., Irizarry RA, Dudoit S. Bioinformatics 20 and Computational Biology Solutions Using R and Bioconductor. Springer 2005. 41. Bauer DF. Constructing confidence sets using rank statistics. Journal of the American Statistical Association 1972;67:687-690. 42. L6nnstedt I. and Speed TP. Replicated microarray data. Statistica Sinica 2002;12:31-46. 25 43. Efron, B. and Tibshirani, R. An Introduction to the Bootstrap. Chapman & Hall. 2005 44. Harraway J. Introductory Statistical Methods and the Analysis of Variance. University of Otago Press 1993. 45. McCabe GP, Moore DS Introduction to the Practice of Statistics W.H. 30 Freeman & Co. 2005 46. Casella G, Berger RL Statistical Inference Wadsworth 2001 47. McLaughlan GJ, Do K, Ambroise C Analyzing Microarray Gene Expression Data (Wiley Series in Probability and Statistics) 2004 129 WO 2007/073220 PCT/NZ2006/000343 48. Wright GW, Simon RM A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics 2003;19:2448-2455 49. Hastie T, Tibshirani R, Friedman J The Elements of Statistical Learning Data Mining, Inference and Prediction Springer 2003 5 50. Neter J, Kutner MH, Wasserman W, Nachtsheim CJ, Applied Linear Statistical Models McGraw-Hill/Irwin 1996 51. Venables, WN, Ripley, BD Modem Applied Statistics with S. 4th ed.. Springer 2002. 52. Ripley, B. D. Pattern Recognition and Neural Networks Cambridge University 10 Press 1996 53. Cristianini N, Shawe-Taylor J An Introduction to Support Vector Machines (and other kernel-based learning methods) Cambridge University Press 2000 54. Breiman L, Friedman J, Stone CJ, Olshen RA Classification and Regression Trees Chapman & Hall/CRC 1984 15 55. Good, PI Resampling Methods: A Practical Guide to Data Analysis Birkhauser 1999 Wherein in the description reference has been made to integers or components having known equivalents, such equivalents are herein incorporated as if individually set 20 fourth. Although the invention has been described by way of example and with reference to possible embodiments thereof, it is to be appreciated that improvements and/or modifications may be made without departing from the scope thereof. 25 130

Claims (18)

1. A prognostic signature for determining progression of CRC, comprising two or more genes selected from Tables 1 and 2. 5

2. The signature of claim 1, selected from any one of the signatures in any one of Tables 3, 4 or Table 9.

3. A device for determining prognosis of CRC, comprising: 10 a substrate having one or more locations thereon, each location having two or more oligonucleotides thereon, each oligonucleotide selected from the group of genes from Tables 1 and 2.

4. The device of claim 3, wherein said the two or more oligonucleotides are a 15 prognostic signature selected from in any one of Tables 3, 4 or Table 9.

5. A method for determining the prognosis of CRC in a patient, comprising the steps of; 20 (i) determining the expression level of a prognostic signature comprising two or more genes from Tables 1 and 2 in CRC tumour sample from the patient, 25 (ii) applying a predictive model, established by applying a predictive method to expressions levels of the predictive signature in recurrent and non-recurrent tumour samples, (iii) establishing a prognosis. 30

6. The method of claim 5, wherein the signature is selected from any one of Tables 3, 4 or Table 9.

7. The method of claim 5, wherein said predictive method is selected from the 35 group consisting of linear models, support vector machines, neural networks, classification and regression trees, ensemble learning methods, discriminant analysis, nearest neighbor method, bayesian networks, independent components analysis.

8. The method of any one of claims 5 to 7, wherein the step of determining the 40 expression level of a prognostic signature is carried out by detecting the expression level of mRNA of each gene.

9. The method of any one of claims 5 to 7, wherein the step of determining the expression level of a prognostic signature is carried out by detecting the expression 45 level of cDNA of each gene.

10. The method of claim 9, wherein the step of determining the expression level of a prognostic signature is carried out using a nucleotide complementary to at least a portion of said cDNA. 50 131 WO 2007/073220 PCT/NZ2006/000343

11. The method of claim 8, wherein the step of determining the expression level of a prognostic signature is carried out using qPCR method using a forward primer and a reverse primer. 5

12. The method of claim 8, wherein the step of determining the expression level of a prognostic signature is carried out using a device according to claim 3 or claim 4.

13. The method of any one of claims 5 to 7, wherein the step of determining the expression level of a prognostic signature is carried out by detecting the expression 10 level of the protein of each marker.

14. The method of any one of claims 5 to 7, wherein the step of determining the expression level of a prognostic signature is carried out by detecting the expression level of the peptide of each marker. 15

15. The method of claim 12 or claim 13, wherein said step of detecting is carried out using an antibody directed against each marker.

16. The method of any one of claims 12 to 14, wherein said step of detecting is 20 carried out using a sandwich-type immunoassay method.

17. The method of any one of claims 12 to 15, wherein said antibody is a monoclonal antibody. 25

18. The method of any one of claims 12 to 15, wherein said antibody is a polyclonal antiserum. 132