Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
  • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• This invention relates, in part, to newly developed assays for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating cancers, particularly prostate cancer.
• Cancer of the prostate is the most prevalent malignancy in adult males, excluding skin cancer, and is an increasingly prevalent health problem in the United States. In 1996, it was estimated that 41,400 deaths would result from this disease in the United States alone, indicating that prostate cancer is second only to lung cancer as the most common cause of death in the same population. If diagnosed and treated early, when the cancer is still confined to the prostate, the chances of cure is significantly higher.
• a common classification of the spread of prostate cancer was developed by the American Urological Association (AUA) .
• the AUA system divides prostate tumors into four stages, A to D.
• Stage A microscopic cancer within prostate, is further subdivided into sub-stages Al and A2.
• Sub-stage Al is a well-differentiated cancer confined to one site within the prostate.
• Treatment is generally observation, radical prostatectomy, or radiation.
• Sub-stage A2 is a moderately to poorly differentiated cancer at multiple sites within the prostate. Treatment is radical prostatectomy or radiation.
• Stage B palpable lump within the prostate, is also further subdivided into sub-stages Bl and B2.
• sub-stage Bl the cancer forms a small nodule in one lobe of the prostate.
• the cancer forms large or multiple nodules, or occurs in both lobes of the prostate.
• Treatment for sub-stages Bl and B2 is either radical prostatectomy or radiation.
• Stage C is a large cancer mass involving most or all of the prostate and is also further subdivided into two stages.
• the cancer forms a continuous mass that may have extended beyond the prostate.
• sub-stage C2 the cancer forms a continuous mass that invades the surrounding tissue.
• Treatment for both these sub- stages is radiation with or without drugs to address the cancer.
• Stage D is metastatic cancer and is also subdivided into two sub-stages.
• sub-stage Dl the cancer appears in the lymph nodes of the pelvis.
• sub-stage D2 the cancer involves tissues beyond lymph nodes . Treatment for both of these sub-stages is systemic drugs to address the cancer as well as pain.
• CSG refers, among other things, to native protein expressed by the gene comprising the polynucleotide sequence of SEQ ID NO:l.
• SEQ ID NO:2 The amino acid sequence of a polypeptide encoded by SEQ ID NO:l is depicted herein as SEQ ID NO:2.
• CSG means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO:l or levels of the gene comprising the polynucleotide sequence of SEQ ID NO:l.
• a method of diagnosing metastatic prostate cancer in a patient having prostate cancer which is not known to have metastasized by identifying a human patient suspected of having prostate cancer that has metastasized; analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissues, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein an increase in CSG levels in the patient versus the normal human control is associated with prostate cancer which has metastasized.
• Also provided by the invention is a method of staging prostate cancer in a human which has such cancer by identifying a human patient having such cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing CSG levels in such cells, tissues, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG is associated with a cancer which is regressing or in remission. Further provided is a method of monitoring prostate cancer in a human having such cancer for the onset of metastasis.
• the method comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissue, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which has metastasized. Further provided is a method of monitoring the change in stage of prostate cancer in a human having such cancer by looking at levels of CSG in a human having such cancer.
• the method comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for CSG; comparing the CSG levels in such cells, tissue, or bodily fluid with levels of CSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in CSG levels in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG is associated with a cancer which is regressing or in remission.
• antibodies targeted against CSG or fragments of such antibodies which can be used to detect or image localization of CSG in a patient for the purpose of detecting or diagnosing a disease or condition.
• Such antibodies can be polyclonal, monoclonal, or omniclonal or prepared by molecular biology techniques.
• the term "antibody”, as used herein and throughout the instant specification is also meant to include aptamers and single- stranded oligonucleotides such as those derived from an in vitro evolution protocol referred to as SELEX and well known to those skilled in the art.
• Antibodies can be labeled with a variety of detectable labels including, but not limited to, radioisotopes and paramagnetic metals.
• antibodies or fragments thereof can also be used as therapeutic agents in the treatment of diseases characterized by expression of CSG.
• the antibody can be used without or with derivatization to a cytotoxic agent such as a radioisotope, enzyme, toxin, drug or a prodrug.
• the present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging and prognosticating cancers by comparing levels of CSG in a human patient with those of CSG in a normal human control.
• levels of CSG means levels of the native protein expressed by the gene comprising the polynucleotide sequence of SEQ ID NO:l.
• the amino acid sequence of a polypeptide encoded by SEQ ID NO:l is depicted herein as SEQ ID NO: 2.
• the native protein being detected may be whole, a breakdown product, a complex of molecules or chemically modified.
• levels of CSG means levels of the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO:l or levels of DNA comprising the polynucleotide sequence of SEQ ID NO:l. Such levels are preferably measured in at least one of cells, tissues and/or bodily fluids, including determination of normal and abnormal levels.
• a diagnostic assay in accordance with the invention for diagnosing over-expression of CSG protein compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of prostate cancer.
• All the methods of the present invention may optionally include measuring the levels of other cancer markers as well as CSG.
• Other cancer markers, in addition to CSG, useful in the present invention will depend on the cancer being tested and are known to those of skill in the art.
• the present invention provides methods for diagnosing the presence of prostate cancer by analyzing for changes in levels of CSG in cells, tissues or bodily fluids compared with levels of CSG in cells, tissues or bodily fluids of preferably the same type from a normal human control , wherein an increase in levels of CSG in the patient versus the normal human control is associated with the presence of prostate cancer.
• a positive result indicating the patient being tested has cancer is one in which cells, tissues or bodily fluid levels of the cancer marker, such as CSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control.
• the cancer marker such as CSG
• the present invention also provides a method of diagnosing metastatic prostate cancer in a patient having prostate cancer which has not yet metastasized for the onset of metastasis.
• a human cancer patient suspected of having prostate cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art.
• determining the presence of CSG levels in cells, tissues or bodily fluid is particularly useful for discriminating between prostate cancer which has not metastasized and prostate cancer which has metastasized.
• Existing techniques have difficulty discriminating between prostate cancer which has metastasized and prostate cancer which has not metastasized. However, proper treatment selection is often dependent upon such knowledge.
• the cancer marker levels measured in such cells, tissues or bodily fluid is CSG.
• Measured levels of CSG are compared with levels of CSG in preferably the same cells, tissue or bodily fluid type of a normal human control. That is, if the cancer marker being observed is just CSG in serum, this level is preferably compared with the level of CSG in serum of a normal human patient.
• An increase in CSG levels in the patient versus the normal human control is associated with prostate cancer which has metastasized.
• a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues or bodily fluid levels of the cancer marker, such as CSG, are at least two times higher, and most preferably are at least five times higher, than in preferably the same cells, tissues or bodily fluid of a normal patient.
• Normal human control as used herein includes a human patient without cancer and/or non cancerous samples from the patient; in the methods for diagnosing or monitoring for metastasis, normal human control may preferably also include samples from a human patient that is determined by reliable methods to have prostate cancer which has not metastasized. Staging
• the invention also provides a method of staging prostate cancer in a human patient.
• the method comprises identifying a human patient having such cancer and analyzing a sample of cells, tissues or bodily fluid from such human patient for CSG.
• the measured CSG levels in the patient are then compared with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which is progressing and a decrease in the levels of CSG (but still increased over true normal levels) is associated with a cancer which is regressing or in remission.
• Moni toring Moni toring
• a method of monitoring prostate cancer in a human patient having such cancer for the onset of metastasis comprises identifying a human patient having prostate cancer that is not known to have metastasized; periodically analyzing cells, tissues or bodily fluid from such human patient for CSG; comparing the CSG levels in such cells, tissues or bodily fluid with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which has metastasized.
• normal human control samples may also include prior patient samples.
• a method of monitoring the change in stage of prostate cancer in a human patient having such cancer is identifying a human patient having prostate cancer that is not known to have metastasized.
• the method comprises identifying a human patient having prostate cancer; periodically analyzing cells, tissues or bodily fluid from such human patient for CSG; comparing the CSG levels in such cells, tissues or bodily fluid with levels of CSG in preferably the same cells, tissues or bodily fluid type of a normal human control, wherein an increase in CSG levels in the human patient versus the normal human control is associated with a cancer which is progressing in stage and a decrease in the levels of CSG is associated with a cancer which is regressing in stage or in remission.
• normal human control samples may also include prior patient samples.
• Monitoring patients for onset of metastasis is periodic and preferably done on a quarterly basis. However, monitoring may be performed more or less frequently depending on the cancer, the particular patient, and the stage of the cancer.
• Assay techniques that can be used to determine levels of gene expression (including protein levels), such as CSG of the present invention, in a sample derived from a patient are well known to those of skill in the art.
• Such assay methods include, without limitation, radioimmunoassays, reverse transcriptase PCR (RT-PCR) assays, immunohistochemistry assays, in si tu hybridization assays, competitive-binding assays, Western Blot analyses, ELISA assays and proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis) and non-gel based approaches such as mass spectrometry or protein interaction profiling.
• ELISAs are frequently preferred to diagnose a gene ' s expressed protein in biological fluids.
• An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to CSG, preferably a monoclonal antibody.
• a reporter antibody generally is prepared which binds specifically to CSG.
• the reporter antibody is attached to a detectable reagent such as radioactive, fluorescent or enzymatic reagent.
• detectable agents such as horseradish peroxidase enzyme and alkaline phosphatase are routinely used in these types of assays.
• antibody specific to CSG is incubated on a solid support, e.g. a polystyrene dish, that binds the antibody. Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin.
• a non-specific protein such as bovine serum albumin.
• the sample to be analyzed is incubated in the dish, during which time CSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer.
• a reporter antibody specifically directed to CSG and linked to a detectable reagent such as horseradish peroxidase is placed in the dish resulting in binding of the reporter antibody to any monoclonal antibody bound to CSG. Unattached reporter antibody is then washed out.
• Reagents for detection of peroxidase activity including a colorimetric substrate are then added to the dish.
• Immobilized peroxidase linked to CSG antibodies produces a colored reaction product.
• the amount of color developed in a given time period is proportional to the amount of CSG protein present in the sample. Quantitative results typically are obtained by reference to a standard curve.
• a competition assay can also be employed wherein antibodies specific to CSG are attached to a solid support. Labeled CSG and a sample derived from the host are then passed over the solid support. The amount of label detected which is attached to the solid support can be correlated to a quantity of CSG in the sample.
• Nucleic acid methods can be used to detect CSG mRNA as a marker for prostate cancer.
• RT-PCR reverse- transcriptase PCR
• cDNA complementary DNA
• RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the mRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence of a specific type of cell.
• Hybridization to clones or oligonucleotides arrayed on a solid support can be used to detect the expression of and quantitate the level of expression of that gene.
• a cDNA encoding the CSG gene is fixed to a substrate.
• the substrate may be of any suitable type including but not limited to glass, nitrocellulose, nylon or plastic.
• At least a portion of the DNA encoding the CSG gene is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA isolated from the tissue of interest.
• Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including, but not limited to, radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed to detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards. The standards can be obtained by in vi tro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
• 2D electrophoresis is a technique well known to those in the art. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by different characteristics usually on polyacrylamide gels.
• proteins are separated by size using an electric current.
• the current acts uniformly on all proteins so that smaller proteins move farther on the gel than larger proteins.
• the second dimension applies a current perpendicular to the first and separates proteins not on the basis of size but on the specific electric charge carried by each protein. Since no two proteins with different sequences are identical on the basis of both size and charge, the result of a 2D separation is a square gel in which each protein occupies a unique spot . Analysis of the spots with chemical or antibody probes or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample .
• Tissue extracts can be obtained from tissue biopsy and autopsy material.
• Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof.
• blood it is meant to include whole blood, plasma, serum or any derivative of blood.
• Antibodies which specifically bind to CSG can also be used in vivo in patients suspected of suffering from prostate cancer. Specifically, antibodies which specifically bind a CSG can be injected into a patient suspected of having prostate cancer for diagnostic and/or therapeutic purposes. The preparation and use of antibodies for in vivo diagnosis is well known in the art. For example, antibody-chelators labeled with Indium-Ill have been described for use in the radioimmunoscintographic imaging of carcinoembryonic antigen expressing tumors (Sumerdon et al . Nucl . Med. Biol . 1990 17:247-254).
• these antibody-chelators have been used in detecting tumors in patients suspected of having recurrent colorectal cancer (Griffin et al . J. Clin. One. 1991 9:631-640).
• Antibodies with paramagnetic ions as labels for use in magnetic resonance imaging have also been described (Lauffer, R.B. Magnetic Resonance in Medicine 1991 22:339- 342) .
• Antibodies directed against CSG can be used in a similar manner. Labeled antibodies which specifically bind CSG can be injected into patients suspected of having prostate cancer for the purpose of diagnosing or staging of the disease status of the patient. The label used will be selected in accordance with the imaging modality to be used.
• radioactive labels such as Indium-111, Technetium-99m or Iodine-131 can be used for planar scans or single photon emission computed tomography (SPECT) .
• Positron emitting labels such as Fluorine-19 can be used in positron emission tomography.
• Paramagnetic ions such as Gadlinium (III) or Manganese (II) can be used in magnetic resonance imaging (MRI) . Localization of the label permits determination of the spread of the cancer. The amount of label within an organ or tissue also allows determination of the presence or absence of cancer in that organ or tissue.
• an antibody which specifically binds CSG can also have a therapeutic benefit .
• the antibody may exert its therapeutic effect alone.
• the antibody can be conjugated to a cytotoxic agent such as a drug, toxin or radionuclide to enhance its therapeutic effect .
• Drug monoclonal antibodies have been described in the art for example by Garnett and Baldwin, Cancer Research 1986 46:2407-2412. The use of toxins conjugated to monoclonal antibodies for the therapy of various cancers has also been described by Pastan et al . Cell 1986 47:641-648.
• Yttrium-90 labeled monoclonal antibodies have been described for maximization of dose delivered to the tumor while limiting toxicity to normal tissues (Goodwin and Meares Cancer Supplement 1997 80:2675-2680).
• Other cytotoxic radionuclides including, but not limited to Copper-67, Iodine- 131 and Rhenium-186 can also be used for labeling of antibodies against CSG.
• Antibodies which can be used in these in vivo methods include polyclonal, monoclonal and omniclonal antibodies and antibodies prepared via molecular biology techniques. Antibody fragments and aptamers and single-stranded oligonucleotides such as those derived from an in vi tro evolution protocol referred to as SELEX and well known to those skilled in the art can also be used.
• CLONTECH PCR-SELECT is a PCR based subtractive hybridization method designed to selectively enrich for cDNAs corresponding to mRNAs differentially expressed between two mRNA populations (Diatchenko et al , Proc. Natl . Acad. Sci . USA, Vol. 93, pp. 6025-6030, 1996). In this method, differentially expressed mRNAs are enriched based on a selective amplification. cDNA is prepared from the two mRNA populations which are to be compared.
• Tester population which is a cDNA population in which the differentially expressed messages are sought
• Driver population which is a cDNA population in which the differentially expressed transcripts are absent or low.
• the tester sample is separated in two parts and different PCR adapters are ligated to the 5' ends.
• Each tester is separately annealed to excess driver in the first annealing and then pooled and again annealed in the second annealing to excess driver.
• sequences common to both populations anneal.
• concentration of high and low abundance messages are normalized since annealing is faster for abundant molecules due to the second order kinetics of hybridization.
• cDNAs unique or overabundant to the tester can anneal together. Such molecules have different adapters at their ends. The addition of additional driver during the second annealing enhances the enrichment of the desired differentially expressed sequences.
• molecules that have different adapters at each end amplify exponentially. Molecules which have identical adapters, or adapters at only one end, or no adapters (driver sequences) either do not amplify or undergo linear amplification. The end result is enrichment for cDNAs corresponding to differentially expressed messages unique to the tester or up regulated in the tester.
• This technique was used to identify transcripts unique to cancer tissues or messages overexpressed in the cancer process.
• pairs of samples isolated from a cancer tissue were used as the "tester", and non-cancer tissue as the "driver” .
• the non-cancer "driver” can be from the same individual and tissue as the tumor (Matched) .
• the "driver” can be from a different individual but the same tissue as the tumor sample (unmatched) .
• the "driver” comprises mixtures of cDNAs derived from non-cancer tissues different from the cancer tissue. This approach allows the identification of transcripts whose expression is specific or up-regulated in the cancer tissue. Such transcripts may or may not be cancer specific in their expression. Subtractive hybridization was carried out using as
• tester a mixture of three RNAs from human adenocarcinomas and as “driver” a mixture of RNAs from five human normal tissues (spleen, pancreas, heart, kidney and small intestine) .
• the subtracted mixture was cloned and two hundred clones were sequenced.
• One of the sequences matched Incyte clone ID 3966820.
• the electronic Northern for this clone showed the highest number of ESTs came from prostate, compared with other tissues (prostate 107 followed by uterus with 20) .
• the PCR-select clone detected a transcript of 1.9 kb by hybridization in Northern blots. Amongst 17 tissues tested prostate showed the highest abundance for this transcript .
• Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5'- 3' nuclease activity of Taq DNA polymerase.
• the method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5' reporter dye and a downstream, 3' quencher dye.
• Taqman internal fluorescent oligonucleotide probe
• the 5' -3' nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, CA, USA) .
• Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency.
• Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or 18S ribosomal RNA (rRNA) is used as this endogenous control.
• GPDH glyceraldehyde-3-phosphate dehydrogenase
• rRNA 18S ribosomal RNA
• Quantitation relative to the "calibrator" can be obtained using the standard curve method or the comparative method
• RNA was extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues.
• first strand cDNA was prepared with reverse transcriptase and the polymerase chain reaction was done using primers and Taqman probes specific to each target gene.
• the results were analyzed using the ABI PRISM 7700 Sequence Detector.
• the absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue.
• Real-Time quantitative PCR was done using the following primers : prol08 Reverse GCCTTCAGCCGTGGGTAGT (SEQ ID NO: 3) prol08 Forward GACAGCGGCTTCACCTTCTC (SEQ ID NO: 4)
• RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.
• the relative levels of expression in Table 1 show the highest mRNA expression in ovary (41.07) and uterus (15.56), two female specific tissues. Except for stomach (11.39) that shows high levels of mRNA for prolO ⁇ , the other tissues including prostate show comparable low levels of expression.
• Table 1 The absolute numbers in Table 1 were obtained analyzing pools of samples of a particular tissue from different individuals. They can not be compared to the absolute numbers originated from RNA obtained from tissue samples of a single individual in Table 2.
• the absolute numbers depicted in Table 2 are relative levels of expression of the CSG prol08 in 70 pairs of matching samples. All the values are compared to normal pancreas (calibrator) .
• a matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual. Unmatched samples were used for prostatitis (prostatitis 1 and 2) and Benign Prostate Hyperplasia (BPH 1 to 6) .
• Table 2 shows the results for the analysis of 148 samples distributed in 14 different tissue types. Tables 1 and 2 represent a combined total of 159 samples in 16 different tissue types.
• the level of mRNA expression in cancer samples was compared with the isogenic normal adjacent tissue from the same individual . This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent) .
• Table 2 shows overexpression of the CSG prol08 in 13 of 13 prostate cancer tissues compared with their respective normal adjacent (prostate samples #1 to #13) . Thus, there was overexpression in the cancer tissue for 100% of the prostate matching samples tested.
• the level of tissue specificity, plus the mRNA overexpression in 100% of the prostate matching samples tested are indicative of the CSG prol08 being a diagnostic marker for prostate cancer.

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