WO2021024009A1 - Procédés et compositions pour fournir une évaluation du cancer du côlon à l'aide de biomarqueurs protéiques - Google Patents

Procédés et compositions pour fournir une évaluation du cancer du côlon à l'aide de biomarqueurs protéiques Download PDF

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WO2021024009A1
WO2021024009A1 PCT/IB2019/000896 IB2019000896W WO2021024009A1 WO 2021024009 A1 WO2021024009 A1 WO 2021024009A1 IB 2019000896 W IB2019000896 W IB 2019000896W WO 2021024009 A1 WO2021024009 A1 WO 2021024009A1
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colon cancer
ferr
subject
cea
dhea
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PCT/IB2019/000896
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English (en)
Inventor
Shiying Hao
Limin Chen
Bruce Xuefeng Ling
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Shanghai Yunxiang Medical Technology Co., Ltd.
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Priority to PCT/IB2019/000896 priority Critical patent/WO2021024009A1/fr
Publication of WO2021024009A1 publication Critical patent/WO2021024009A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57419—Specifically defined cancers of colon

Definitions

  • This disclosure of provisional patent application pertains to methods and compositions for providing a colon cancer assessment using CEA, DHEA.S, FERR and other markers.
  • Colon cancer is the fourth most common cancer worldwide.
  • One of the most important factors to improve prognostic effects of colon cancer is the diagnosis at early stages, where a 5-year relative survival rate greater than 90% can be achieved. It is crucial to be noted that colon cancer often develops in a step-wise adenoma-carcinoma manner; in this way, most patients could be cured if the disease was detected and resected at an early stage before the disease progressed into a late, irreversible stage. Therefore, early detection of colon cancer is one of the key prerequisites for successful treatment and reduction of mortality from this disease.
  • Colon cancer markers for obtaining a colon cancer marker level representation for a sample are provided. These compositions and methods find use in a number of applications, including, for example, diagnosing colon cancer, prognosing a colon cancer, monitoring a subject with colon cancer, and determining a treatment for colon cancer. In addition, systems, devices and kits thereof that find use in practicing the subject methods are provided.
  • a panel of colon cancer markers comprising one or more colon cancer markers selected from the group consisting of the ratio of CEA to FERR (CEA/FERR), the ratio of dehydroepiandrosterone sulfate (DHEA.S) to FERR (DHEA.S/FERR), and the geometric mean of the above two ratios.
  • a method for providing a colon cancer marker level representation for a subject.
  • the method comprises evaluating a panel of colon cancer markers in a blood sample from a subject to determine the level of each colon cancer marker in the blood sample; and obtaining the colon cancer marker level representation based on the level of each colon cancer marker in the panel.
  • the panel comprises the ratio of CEA to FERR (CEA/FERR), the ratio of dehydroepiandrosterone sulfate (DHEA.S) to FERR (DHEA.S/FERR), and/or the geometric mean of the above two ratios.
  • the method further comprises providing a report of the colon cancer marker level representation.
  • the colon cancer marker representation is a colon cancer score.
  • a method for providing a colon cancer assessment for a subject.
  • the colon cancer assessment is a diagnosis of colon cancer.
  • the method comprises obtaining a colon cancer marker level representation for a sample from a subject, e.g. as described above or elsewhere herein, and providing a colon cancer diagnosis for the subject based on the colon cancer marker level representation.
  • the method further comprises comparing the colon cancer marker level representation to a colon cancer phenotype determination element, and providing a colon cancer diagnosis for the subject based on the comparison.
  • the subject has symptoms of colon cancer.
  • the subject is asymptomatic for colon cancer.
  • the subject has one or more risk factors associated with colon cancer.
  • the subject has no risk factors associated with colon cancer.
  • the methods may be particularly suitable for certain subjects, such as those that have a history of nonadvanced adenoma and/or colon cancer, a risk to develop colon cancer, and a tendency to develop colon cancer.
  • the subject can be administered to a procedure that helps ameliorate the colon cancer.
  • procedures include, without limitation, medications to remove colorectal lesions.
  • kits for making a colon cancer assessment for a sample.
  • the colon cancer is a colon cancer diagnosis.
  • the kit comprises one or more detection elements for measuring the amount of marker in a sample for a panel of colon cancer markers comprising carcinoembryonic antigen (CEA) and/or ferritin (FERR).
  • CEA carcinoembryonic antigen
  • FFERR ferritin
  • the kit comprises one or more detection elements for measuring the amount of marker in a sample for a panel of colon cancer markers comprising the ratio of CEA to FERR (CEA/FERR), the ratio of dehydroepiandrosterone sulfate (DHEA.S) to FERR (DHEA.S/FERR), and/or the geometric mean of the above two ratios.
  • the kit further comprises a colon cancer phenotype determination element.
  • Figure 1 Study outline of the discovery and validation process of colon cancer biomarkers.
  • Figure 2 Boxplot display of the concentration of FERR in blood in control, tumor and cancer groups, respectively. P was calculated using Student's t-test. The ratio of the median values in the cancer group to the median values in the control group is 0.57.
  • Figure 3 Boxplot display of the concentration of CEA in blood in control, tumor and cancer groups, respectively. P was calculated using Student's t-test. The ratio of the median values of the marker in the cancer group to the median values in the control group is 1.21.
  • Figure 4 Boxplot display of the ratio of CEA to FERR in blood in control, tumor and cancer groups, respectively. P was calculated using Student's t-test. The ratio of the median values of the marker ratio in the cancer group to the median values in the control group is 2.19.
  • Figure 5 Boxplot display of the ratio of CEA to FERR in control, tumor and cancer groups, respectively. P was calculated using Student's t-test. The ratio of the median values of the marker ratio in the cancer group to the median values in the control group is 1.52.
  • Figure 6 Boxplot display of the geometric mean of the ratio of CEA to FERR and the ratio of DHEA.S to FERR in control, tumor and cancer groups, respectively. P was calculated using Student's t-test. The ratio of the median values of the geometric mean in the cancer group to the median values in the control group is 1.83.
  • Colon cancer markers, colon cancer marker panels, and methods for obtaining a colon cancer marker level representation for a sample are provided. These compositions and methods find use in a number of applications, including, for example, diagnosing colon cancer genes, prognosing a colon cancer genes, monitoring a subject with colon cancer, and determining a treatment for colon cancer. In addition, systems, devices and kits thereof that find use in practicing the subject methods are provided.
  • aspects of the subject invention include methods, compositions, systems and kits that find use in providing a colon cancer assessment, e.g. diagnosing, prognosing, monitoring, and/or treating colon cancer in a subject.
  • colon cancer it is meant a multisystem complication of colon cancer. If unaddressed, nonadvanced adenoma can lead to colon cancer, and an early-stage colon cancer can develop into a late-stage one.
  • diagnostic a colon cancer or “providing a colon cancer diagnosis,” it is generally meant providing a colon cancer determination, e.g. a determination as to whether a subject (e.g.
  • a subject that has clinical symptoms of colon cancer a subject that is asymptomatic for colon cancer but has risk factors associated with colon cancer, a subject that is asymptomatic for colon cancer and has no risk factors associated with colon cancer
  • is presently affected by colon cancer a classification of the subject's colon cancer into a subtype of the disease or disorder; a determination of the severity of colon cancer; and the like.
  • prognosing a colon cancer, or “providing a colon cancer prognosis,” it is generally meant providing a colon cancer prediction, e.g. a prediction of a subject's susceptibility, or risk, of developing colon cancer; a prediction of the course of disease progression and/or disease outcome, e.g.
  • monitoring it is generally meant monitoring a subject's condition, e.g. to inform a colon cancer diagnosis, to inform a colon cancer prognosis, to provide information as to the effect or efficacy of a colon cancer treatment, and the like.
  • treating it is meant prescribing or providing any treatment of a colon cancer in a mammal, and includes: (a) preventing the colon cancer from occurring in a subject which may be predisposed to colon cancer but has not yet been diagnosed as having it; (b) inhibiting the colon cancer, i.e., arresting its development; or (c) relieving the colon cancer, i.e., causing regression of the colon cancer.
  • compositions useful for providing a colon cancer assessment will be described first, followed by methods, systems and kits for their use.
  • colon cancer markers and panels of colon cancer markers are provided.
  • a colon cancer marker it is meant a molecular entity whose representation in a sample is associated with a colon cancer phenotype.
  • a colon cancer marker may be differentially represented, i.e. represented at a different level, in a sample from an individual that will develop or has developed colon cancer as compared to a healthy individual.
  • an elevated level of marker is associated with the colon cancer phenotype.
  • the concentration of marker in a sample may be 1.5- fold, 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, or greater in a sample associated with the colon cancer phenotype than in a sample not associated with the colon cancer phenotype.
  • a reduced level of marker is associated with the colon cancer phenotype.
  • the concentration of marker in a sample may be 10% less, 20% less, 30% less, 40% less, 50% less or more in a sample associated with the colon cancer phenotype than in a sample not associated with the colon cancer phenotype.
  • Colon cancer markers may include proteins associated with colon cancer and their corresponding genetic sequences, i.e. mRNA, DNA, etc.
  • a “gene” or “recombinant gene” it is meant a nucleic acid comprising an open reading frame that encodes for the protein.
  • a gene may optionally include its natural promoter (i.e., the promoter with which the exons and introns of the gene are operably linked in a non-recombinant cell, i.e., a naturally occurring cell), and associated regulatory sequences, and may or may not have sequences upstream of the AUG start site, and may or may not include untranslated leader sequences, signal sequences, downstream untranslated sequences, transcriptional start and stop sequences, polyadenylation signals, translational start and stop sequences, ribosome binding sites, and the like.
  • the inventors have identified a number of molecular entities that are associated with colon cancer and that find use in combination (i.e. as a panel) in providing a colon cancer assessment, e.g. diagnosing colon cancer, prognosing a colon cancer, monitoring a subject with colon cancer, determining a treatment for a subject affected with colon cancer, and the like.
  • CEA carcinoembryonic antigen
  • FERR ferritin
  • DHEA/FERR dehydroepiandrosterone sulfate
  • DHEA.S dehydroepiandrosterone sulfate
  • DHEA.S/FERR the geometric mean of the above two ratios.
  • colon cancer panels By a “panel” of colon cancer markers it is meant two or more colon cancer markers, e.g. 2 or more, 3 or more, 4 or more, or 5 or more markers, whose levels, when considered in combination, find use in providing a colon cancer assessment, e.g. making a colon cancer diagnosis, prognosis, monitoring, and/or treatment.
  • the colon cancer panel may comprise the ratio of CEA to FERR (CEA/FERR), the ratio of DHEA.S to FERR (DHEA.S/FERR), and/or the geometric mean of the above two ratios.
  • CEA carcinoembryonic antigen
  • FERR ferritin
  • DHEA.S dehydroepiandrosterone sulfate
  • DHEA.S/FERR dehydroepiandrosterone sulfate
  • the colon cancer panel may comprise the ratio of CEA to FERR (CEA/FERR), the ratio of DHEA.S to FERR (DHEA.S/FERR), and/or the geometric mean of the above two ratios.
  • colon cancer markers that find use as colon cancer panels in the subject methods may be readily identified by the ordinarily skilled artisan using any convenient statistical methodology, e.g. as known in the art or described in the working examples herein.
  • the panel of analytes may be selected by combining genetic algorithm (GA) and all paired (AP) support vector machine (SVM) methods for colon cancer classification analysis.
  • G genetic algorithm
  • AP all paired
  • SVM support vector machine
  • Predictive features are automatically determined, e.g. through iterative GA/SVM, leading to very compact sets of non-redundant colon cancer-relevant analytes with the optimal classification performance. While different classifier sets will typically harbor only modest overlapping gene features, they will have similar levels of accuracy in providing a colon cancer assessment to those described above and in the working examples herein.
  • a colon cancer marker level representation it is meant a representation of the levels of one or more of the subject colon cancer marker(s), e.g, a panel of colon cancer markers, in a biological sample from a subject.
  • the term "biological sample” encompasses a variety of sample types obtained from an organism and can be used in a diagnostic, prognostic, or monitoring assay.
  • the term encompasses blood and other liquid samples of biological origin or cells derived therefrom and the progeny thereof.
  • the term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components.
  • the term encompasses a clinical sample, and also includes cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.
  • Clinical samples for use in the methods of the invention may be obtained from a variety of sources, particularly blood samples.
  • Sample sources of particular interest include blood samples or preparations thereof, e.g., whole blood, or serum or plasma, and urine.
  • a suitable initial source for the human sample is a blood sample.
  • the sample employed in the subject assays is generally a blood-derived sample.
  • the blood derived sample may be derived from whole blood or a fraction thereof, e.g., serum, plasma, etc., where in some embodiments the sample is derived from blood, allowed to clot, and the serum separated and collected to be used to assay.
  • the sample is a serum or serum-derived sample. Any convenient methodology for producing a fluid serum sample may be employed.
  • the method employs drawing venous blood by skin puncture (e.g., finger stick, venipuncture) into a clotting or serum separator tube, allowing the blood to clot, and centrifuging the serum away from the clotted blood. The serum is then collected and stored until assayed. Once the patient derived sample is obtained, the sample is assayed to determine the level of colon cancer marker(s).
  • a sample can be used directly, frozen, or maintained in appropriate culture medium for short periods of time.
  • the samples will be from human subjects, although animal models may find use, e.g. equine, bovine, porcine, canine, feline, rodent, e.g. mice, rats, hamster, primate, etc. Any convenient tissue sample that demonstrates the differential representation in a patient with colon cancer of the one or more colon cancer markers disclosed herein may be evaluated in the subject methods.
  • a suitable sample source will be derived from fluids into which the molecular entity of interest, i.e. the RNA transcript or protein, has been released.
  • the subject sample may be treated in a variety of ways so as to enhance detection of the one or more colon cancer markers.
  • the red blood cells may be removed from the sample (e.g., by centrifugation) prior to assaying.
  • Such a treatment may serve to reduce the non-specific background levels of detecting the level of a colon cancer marker using an affinity reagent.
  • Detection of a colon cancer marker may also be enhanced by concentrating the sample using procedures well known in the art (e.g. acid precipitation, alcohol precipitation, salt precipitation, hydrophobic precipitation, filtration.
  • the pH of the test and control samples will be adjusted to, and maintained at, a pH which approximates neutrality. Such a pH adjustment will prevent complex formation, thereby providing a more accurate quantitation of the level of marker in the sample.
  • the pH of the sample is adjusted and the sample is concentrated in order to enhance the detection of the marker.
  • the level(s) of colon cancer marker(s) in the biological sample from an individual are evaluated.
  • the level of one or more colon cancer markers in the subject sample may be evaluated by any convenient method.
  • colon cancer gene expression levels may be detected by measuring the levels/amounts of one or more nucleic acid transcripts, e.g. mRNAs, of one or more colon cancer genes.
  • Protein markers may be detected by measuring the levels/amounts of one or more proteins/polypeptides.
  • the terms “evaluating”, “assaying”, “measuring”, “assessing,” and “determining” are used interchangeably to refer to any form of measurement, including determining if an element is present or not, and including both quantitative and qualitative determinations. Evaluating may be relative or absolute.
  • the level of at least one colon cancer marker may be evaluated by detecting in a sample the amount or level of one or more proteins/polypeptides or fragments thereof to arrive at a protein level representation.
  • protein and “polypeptide” as used in this application are interchangeable.
  • Polypeptide refers to a polymer of amino acids (amino acid sequence) and does not refer to a specific length of the molecule. Thus peptides and oligopeptides are included within the definition of polypeptide.
  • This term also refers to or includes post-translationally modified polypeptides, for example, glycosylated polypeptide, acetylated polypeptide, phosphorylated polypeptide and the like. Included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring.
  • any convenient protocol for evaluating protein levels may be employed wherein the level of one or more proteins in the assayed sample is determined.
  • one representative and convenient type of protocol for assaying protein levels is ELISA.
  • ELISA and ELISA-based assays for example, electrochemiluminescence (ECL), one or more antibodies specific for the proteins of interest may be immobilized onto a selected solid surface, preferably a surface exhibiting a protein affinity such as the wells of a polystyrene microtiter plate.
  • the assay plate wells are coated with a non-specific "blocking" protein that is known to be antigenically neutral with regard to the test sample such as bovine serum albumin (BSA), casein or solutions of powdered milk.
  • BSA bovine serum albumin
  • the immobilizing surface is contacted with the sample to be tested under conditions that are conducive to immune complex (antigen/antibody) formation.
  • Such conditions include diluting the sample with diluents such as BSA or bovine gamma globulin (BGG) in phosphate buffered saline (PBS)/Tweenor PBSATriton-X 100, which also tend to assist in the reduction of nonspecific background, and allowing the sample to incubate for about 2-4 hrs at temperatures on the order of about 25°-27°C (although other temperatures may be used). Following incubation, the antisera-contacted surface is washed so as to remove non-immunocomplexed material.
  • An exemplary washing procedure includes washing with a solution such as PBS/Tween, PBS/Triton-X 100, or borate buffer.
  • the occurrence and amount of immunocomplex formation may then be determined by subjecting the bound immunocomplexes to a second antibody having specificity for the target that differs from the first antibody and detecting binding of the second antibody.
  • the second antibody will have an associated enzyme, e.g. urease, peroxidase, or alkaline phosphatase, which will generate a color precipitate upon incubating with an appropriate chromogenic substrate.
  • a urease or peroxidase-conjugated anti-human IgG may be employed, for a period of time and under conditions which favor the development of immunocomplex formation (e.g., incubation for 2 hrs at room temperature in a PBS-containing solution such as PBS/Tween).
  • the amount of label is quantified, for example by incubation with a chromogenic substrate such as urea and bromocresol purple in the case of a urease label or 2,2'-azino-di-(3-ethyl- benzthiazoline)-6-sulfonic acid (ABTS) and H2O2, in the case of a peroxidase label. Quantitation is then achieved by measuring the degree of color generation, e.g., using a visible spectrum spectrophotometer.
  • a chromogenic substrate such as urea and bromocresol purple in the case of a urease label or 2,2'-azino-di-(3-ethyl- benzthiazoline)-6-sulfonic acid (ABTS) and H2O2
  • Quantitation is then achieved by measuring the degree of color generation, e.g., using a visible spectrum spectrophotometer.
  • the preceding format may be altered by first binding the sample to the assay plate. Then, primary antibody is incubated with the assay plate, followed by detecting of bound primary antibody using a labeled second antibody with specificity for the primary antibody.
  • the solid substrate upon which the antibody or antibodies are immobilized can be made of a wide variety of materials and in a wide variety of shapes, e.g., microtiter plate, microbead, dipstick, resin particle, etc.
  • the substrate may be chosen to maximize signal to noise ratios, to minimize background binding, as well as for ease of separation and cost. Washes may be effected in a manner most appropriate for the substrate being used, for example, by removing a bead or dipstick from a reservoir, emptying or diluting a reservoir such as a microtiter plate well, or rinsing a bead, particle, chromatograpic column or filter with a wash solution or solvent.
  • non-ELISA based-methods for measuring the levels of one or more proteins in a sample may be employed.
  • Representative examples include but are not limited to mass spectrometry, proteomic arrays, xMAPTM microsphere technology, flow cytometry, western blotting, and immunohistochemistry.
  • the level of at least one colon cancer marker may be evaluated by detecting in a subject sample the amount or level of one or more RNA transcripts or a fragment thereof encoded by the gene of interest to arrive at a nucleic acid marker representation.
  • the level of nucleic acids in the sample may be detected using any convenient protocol. While a variety of different manners of detecting nucleic acids are known, such as those employed in the field of differential gene expression analysis, one representative and convenient type of protocol for generating marker representations is array-based gene expression profiling protocols. Such applications are hybridization assays in which a nucleic acid that displays "probe" nucleic acids for each of the genes to be assayed/profiled in the marker representation to be generated is employed.
  • a sample of target nucleic acids is first prepared from the initial nucleic acid sample being assayed, where preparation may include labeling of the target nucleic acids with a label, e.g., a member of signal producing system.
  • a label e.g., a member of signal producing system.
  • the sample is contacted with the array under hybridization conditions, whereby complexes are formed between target nucleic acids that are complementary to probe sequences attached to the array surface. The presence of hybridized complexes is then detected, either qualitatively or quantitatively.
  • Specific hybridization technology which may be practiced to generate the marker representations employed in the subject methods includes the technology described in U.S. Patent Nos.: 5,143,854; 5,288,644; 5,324,633; 5,432,049; 5,470,710; 5,492,806; 5,503,980; 5,510,270; 5,525,464; 5,547,839; 5,580,732; 5,661 ,028; 5,800,992; the disclosures of which are herein incorporated by reference; as well as WO 95/21265; WO 96/31622; WO 97/10365; WO 97/27317; EP 373203; and EP 785280.
  • an array of "probe" nucleic acids that includes a probe for each of the phenotype determinative genes whose expression is being assayed is contacted with target nucleic acids as described above. Contact is carried out under hybridization conditions, e.g., stringent hybridization conditions, and unbound nucleic acid is then removed.
  • hybridization conditions e.g., stringent hybridization conditions
  • unbound nucleic acid is then removed.
  • stringent assay conditions refers to conditions that are compatible to produce binding pairs of nucleic acids, e.g., surface bound and solution phase nucleic acids, of sufficient complementarity to provide for the desired level of specificity in the assay while being less compatible to the formation of binding pairs between binding members of insufficient complementarity to provide for the desired specificity. Stringent assay conditions are the summation or combination (totality) of both hybridization and wash conditions.
  • the resultant pattern of hybridized nucleic acid provides information regarding expression for each of the genes that have been probed, where the expression information is in terms of whether or not the gene is expressed and, typically, at what level, where the expression data, i.e., marker representation (e.g., in the form of a transcriptosome), may be both qualitative and quantitative.
  • expression information is in terms of whether or not the gene is expressed and, typically, at what level, where the expression data, i.e., marker representation (e.g., in the form of a transcriptosome), may be both qualitative and quantitative.
  • non-array based methods for quantitating the level of one or more nucleic acids in a sample may be employed, including those based on amplification protocols, e.g., Polymerase Chain Reaction (PCR)-based assays, including quantitative PCR, reverse-transcription PCR (RT-PCR), real-time PCR, and the like.
  • PCR Polymerase Chain Reaction
  • RT-PCR reverse-transcription PCR
  • real-time PCR real-time PCR
  • the resultant data provides information regarding levels in the sample for each of the markers that have been probed, wherein the information is in terms of whether or not the marker is present and, typically, at what level, and wherein the data may be both qualitative and quantitative.
  • the methods provide a reading or evaluation, e.g., assessment, of whether or not the target marker, e.g., nucleic acid or protein, is present in the sample being assayed.
  • the methods provide a quantitative detection of whether the target marker is present in the sample being assayed, i.e., an evaluation or assessment of the actual amount or relative abundance of the target analyte, e.g., nucleic acid or protein in the sample being assayed.
  • the quantitative detection may be absolute or, if the method is a method of detecting two or more different analytes, e.g., target nucleic acids or protein, in a sample, relative.
  • the term "quantifying" when used in the context of quantifying a target analyte, e.g., nucleic acid(s) or protein(s), in a sample can refer to absolute or to relative quantification.
  • Absolute quantification may be accomplished by inclusion of known concentration(s) of one or more control analytes and referencing the detected level of the target analyte with the known control analytes (e.g., through generation of a standard curve).
  • relative quantification can be accomplished by comparison of detected levels or amounts between two or more different target analytes to provide a relative quantification of each of the two or more different analytes, e.g., relative to each other.
  • the measurement(s) may be analyzed in any of a number of ways to obtain a colon cancer marker level representation.
  • the measurements of the one or more colon cancer markers may be analyzed individually to develop a colon cancer profile.
  • a “colon cancer profile” is the normalized level of one or more colon cancer markers in a subject sample, for example, the normalized level of serological protein concentrations in a subject sample.
  • a profile may be generated by any of a number of methods known in the art.
  • the level of each marker may be log2 transformed and normalized relative to the expression of a selected housekeeping gene, or relative to the signal across a whole panel, etc. Other methods of calculating a colon cancer profile will be readily known to the ordinarily skilled artisan.
  • the measurements of a panel of colon cancer markers may be analyzed collectively to arrive at a single colon cancer score.
  • a colon cancer score it is meant a single metric value that represents the weighted levels of each of the colon cancer markers in the colon cancer panel.
  • the subject method comprises detecting the level of markers of a colon cancer panel in the sample, and calculating a colon cancer score based on the weighted levels of the colon cancer markers.
  • a colon cancer score for a patient sample may be calculated by any of a number of methods and algorithms known in the art for calculating biomarker scores. For example, weighted marker levels, e.g.
  • log 2 transformed and normalized marker levels that have been weighted by, e.g., multiplying each normalized marker level to a weighting factor, may be totaled and in some cases averaged to arrive at a single value representative of the panel of colon cancer markers analyzed.
  • the weighting factor, or simply "weight" for each marker in a panel may be a reflection of the change in analyte level in the sample.
  • the analyte level of each colon cancer marker may be log transformed and weighted either as 1 (for those markers that are increased in level in colon cancer) or -1 (for those markers that are decreased in level in colon cancer), and the ratio between the sum of increased markers as compared to decreased markers determined to arrive at a colon cancer signature.
  • the weights may be reflective of the importance of each marker to the specificity, sensitivity and/or accuracy of the marker panel in making the diagnostic, prognostic, or monitoring assessment. Such weights may be determined by any convenient statistical machine learning methodology, e.g.
  • PCA Principle Component Analysis
  • SVMs support vector machines
  • random forests of the dataset from which the sample was obtained
  • weights for each marker are defined by the dataset from which the patient sample was obtained. In other instances, weights for each marker may be defined based on a reference dataset, or "training dataset”.
  • the expression, e.g. polypeptide level, of only one marker is evaluated to produce a marker level representation.
  • the levels of two or more, i.e. a panel, markers is evaluated. Accordingly, in the subject methods, the expression of at least one marker in a sample is evaluated.
  • the evaluation that is made may be viewed as an evaluation of the proteome, as that term is employed in the art.
  • the subject methods of determining or obtaining a colon cancer marker representation for a subject further comprise providing the colon cancer marker representation as a report.
  • the subject methods may further include a step of generating or outputting a report providing the results of a colon cancer marker evaluation in the sample, which report can be provided in the form of an electronic medium (e.g., an electronic display on a computer monitor), or in the form of a tangible medium (e.g., a report printed on paper or other tangible medium). Any form of report may be provided, e.g. as known in the art or as described in greater detail below.
  • Colon cancer marker level representations so obtained find many uses.
  • the marker level representation may be employed to diagnose a colon cancer; that is, to provide a determination as to whether a subject is affected by colon cancer, the type of colon cancer, the severity of colon cancer, etc.
  • the subject may present with clinical symptoms of colon cancer.
  • subject may be asymptomatic for colon cancer but has risk factors associated with colon cancer.
  • the subject may be asymptomatic for colon cancer and have no risk factors associated with colon cancer.
  • the colon cancer marker level representation may be employed to prognose a colon cancer; that is, to provide a colon cancer prognosis.
  • the colon cancer marker level representation may be used to predict a subject's susceptibility, or risk, of developing colon cancer.
  • the colon cancer marker level representation may be used to predict the course of disease progression and/or disease outcome, e.g. expected onset of the colon cancer, expected duration of the colon cancer, expectations as to whether the nonadvanced adenoma will develop into colon cancer, whether an early-stage colon cancer will develop into a late-stage one, etc.
  • the colon cancer marker level representation may be used to predict a subject's responsiveness to treatment for the colon cancer, e.g., a positive response, a negative response, or no response at all.
  • the colon cancer marker level representation may be employed to monitor a colon cancer.
  • monitoring a colon cancer, it is generally meant monitoring a subject's condition, e.g. to inform a colon cancer diagnosis, to inform a colon cancer prognosis, to provide information as to the effect or efficacy of a colon cancer treatment, and the like.
  • the colon cancer marker level representation may be employed to determine a treatment for a subject.
  • treatment means “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease.
  • the therapeutic agent may be administered before, during or after the onset of disease or injury.
  • the treatment of ongoing disease where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest.
  • the subject therapy may be administered prior to the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.
  • the terms "individual,” “subject,” “host,” and “patient,” are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans.
  • Colon cancer genes treatments are well known in the art, and may include bed rest, drinking extra water, a low salt diet, medicine to control blood pressure, corticosteroids, inducing pregnancy, and the like.
  • the subject methods of providing a colon cancer assessment may comprise comparing the obtained colon cancer marker level representation to a colon cancer phenotype determination element to identify similarities or differences with the phenotype determination element, where the similarities or differences that are identified are then employed to provide the colon cancer assessment, e.g. diagnose the colon cancer, prognose the colon cancer, monitor the colon cancer, determine a colon cancer treatment, etc.
  • a phenotype determination element it is meant an element, e.g. a tissue sample, a marker profile, a value (e.g.
  • a phenotype in this instance, a colon cancer phenotype
  • a colon cancer phenotype may be used to determine the phenotype of the subject, e.g. if the subject is healthy or is affected by colon cancer, if the subject has a nonadvanced adenoma that is likely to progress to colon cancer, if the subject has an early- stage colon cancer that is likely to progress to a late-stage one, if the subject has a colon cancer that is responsive to therapy, etc.
  • a colon cancer phenotype determination element may be a sample from an individual that has or does not have colon cancer, which may be used, for example, as a reference/control in the experimental determination of the marker level representation for a given subject.
  • a colon cancer phenotype determination element may be a marker level representation, e.g. marker profile or score, which is representative of a colon cancer state and may be used as a reference/control to interpret the marker level representation of a given subject.
  • the phenotype determination element may be a positive reference/control, e.g., a sample or marker level representation thereof from a subject that has colon cancer, or that will develop colon cancer, or that has colon cancer that is manageable by known treatments, or that has colon cancer that has been determined to be responsive only to certain kind(s) of treatment.
  • the phenotype determination element may be a negative reference/control, e.g. a sample or marker level representation thereof from a subject that has not developed colon cancer.
  • Phenotype determination elements are preferably the same type of sample or, in the case of marker level representations, are obtained from the same type of sample as the sample that was employed to generate the marker level representation for the individual being monitored. For example, if the serum of an individual is being evaluated, the phenotype determination element would preferably be of serum.
  • the obtained marker level representation is compared to a single phenotype determination element to obtain information regarding the individual being tested for colon cancer.
  • the obtained marker level representation is compared to two or more phenotype determination elements.
  • the obtained marker level representation may be compared to a negative reference and a positive reference to obtain confirmed information regarding if the individual will develop colon cancer.
  • the obtained marker level representation may be compared to a reference that is representative of a colon cancer that is responsive to treatment and a reference that is representative of a colon cancer that is not responsive to treatment to obtain information as to whether or not the subject will be responsive to treatment.
  • the comparison of the obtained marker level representation to the one or more phenotype determination elements may be performed using any convenient methodology, where a variety of methodologies are known to those of skill in the art. For example, those of skill in the art of ELISAs or ELISA-like techniques will know that ELISA data may be compared by, e.g. normalizing to standard curves, comparing normalized values, etc.
  • the comparison step results in information regarding how similar or dissimilar the obtained marker level profile is to the control/reference profile(s), which similarity/dissimilarity information is employed to, for example, predict the onset of a colon cancer, diagnose colon cancer, monitor a colon cancer patient, etc.
  • array profiles may be compared by, e.g., comparing digital images of the expression profiles, by comparing databases of expression data, etc.
  • Patents describing ways of comparing expression profiles include, but are not limited to, U.S. Patent Nos. 6,308,170 and 6,228,575, the disclosures of which are herein incorporated by reference. Methods of comparing marker level profiles are also described above. Similarity may be based on relative marker levels, absolute marker levels or a combination of both.
  • a similarity determination is made using a computer having a program stored thereon that is designed to receive input for a marker level representation obtained from a subject, e.g., from a user, determine similarity to one or more reference profiles or reference scores, and return a colon cancer prognosis, e.g., to a user (e.g., lab technician, physician, pregnant individual, etc.). Further descriptions of computer-implemented aspects of the invention are described below.
  • a similarity determination may be based on a visual comparison of the marker level representation, e.g. colon cancer score, to a range of phenotype determination elements, e.g.
  • the above comparison step yields a variety of different types of information regarding the cell/bodily fluid that is assayed. As such, the above comparison step can yield a positive/negative prediction of the onset of colon cancer, a positive/negative diagnosis of colon cancer, a characterization of a colon cancer, information on the responsiveness of a colon cancer to treatment, and the like.
  • the marker level representation is employed directly, i.e. without comparison to a phenotype determination element, to make a colon cancer prognosis, colon cancer diagnosis, or monitor a colon cancer.
  • the subject methods may be employed for a variety of different types of subjects.
  • the subjects are within the class mammalian, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), lagomorpha (e.g. rabbits) and primates (e.g., humans, chimpanzees, and monkeys).
  • the animals or hosts i.e., subjects (also referred to herein as patients), are humans.
  • the subject methods of providing a colon cancer assessment include providing a diagnosis, prognosis, or result of the monitoring.
  • the colon cancer assessment of the present disclosure is provided by providing, i.e. generating, a written report that includes the artisan's assessment, for example, the artisan's determination of whether the patient is currently affected by colon cancer, of the type, stage, or severity of the subject's colon cancer, etc. (a " colon cancer diagnosis”); the artisan's prediction of the patient's susceptibility to developing colon cancer, of the course of disease progression, of the patient's responsiveness to treatment, etc.
  • the subject methods may further include a step of generating or outputting a report providing the results of an artisan's assessment, which report can be provided in the form of an electronic medium (e.g., an electronic display on a computer monitor), or in the form of a tangible medium (e.g., a report printed on paper or other tangible medium). Any form of report may be provided, e.g. as known in the art or as described in greater detail below.
  • a "report,” as described herein, is an electronic or tangible document which includes report elements that provide information of interest relating to the assessment of a subject and its results.
  • a subject report includes at least a colon cancer marker representation, e.g. a colon cancer profile or a colon cancer score, as discussed in greater detail above.
  • a subject report includes at least an artisan's colon cancer assessment, e.g. colon cancer diagnosis, colon cancer prognosis, an analysis of a colon cancer monitoring, a treatment recommendation, etc.
  • a subject report can be completely or partially electronically generated.
  • a subject report can further include one or more of: 1) information regarding the testing facility; 2) service provider information; 3) patient data; 4) sample data; 5) an assessment report, which can include various information including: a) reference values employed, and b) test data, where test data can include, e.g., a protein level determination; 6) other features.
  • the report may include information about the testing facility, which information is relevant to the hospital, clinic, or laboratory in which sample gathering and/or data generation was conducted.
  • Sample gathering can include obtaining a fluid sample, e.g. blood, saliva, urine etc.; a tissue sample, e.g. a tissue biopsy, etc. from a subject.
  • Data generation can include measuring the marker concentration in colon cancer patients versus healthy individuals, i.e. individuals that do not have and/or do not develop colon cancer.
  • This information can include one or more details relating to, for example, the name and location of the testing facility, the identity of the lab technician who conducted the assay and/or who entered the input data, the date and time the assay was conducted and/or analyzed, the location where the sample and/or result data is stored, the lot number of the reagents (e.g., kit, etc.) used in the assay, and the like. Report fields with this information can generally be populated using information provided by the user.
  • the report may include information about the service provider, which may be located outside the healthcare facility at which the user is located, or within the healthcare facility. Examples of such information can include the name and location of the service provider, the name of the reviewer, and where necessary or desired the name of the individual who conducted sample gathering and/or data generation. Report fields with this information can generally be populated using data entered by the user, which can be selected from among pre-scripted selections (e.g., using a drop-down menu). Other service provider information in the report can include contact information for technical information about the result and/or about the interpretive report.
  • the report may include a patient data section, including patient medical history (which can include, e.g., age, race, serotype, prior colon cancer episodes, and any other characteristics), as well as administrative patient data such as information to identify the patient (e.g., name, patient date of birth (DOB), gender, mailing and/or residence address, medical record number (MRN), room and/or bed number in a healthcare facility), insurance information, and the like), the name of the patient's physician or other health professional who ordered the monitoring assessment and, if different from the ordering physician, the name of a staff physician who is responsible for the patient's care (e.g., primary care physician).
  • patient medical history which can include, e.g., age, race, serotype, prior colon cancer episodes, and any other characteristics
  • administrative patient data such as information to identify the patient (e.g., name, patient date of birth (DOB), gender, mailing and/or residence address, medical record number (MRN), room and/or bed number in a healthcare facility), insurance information, and the like
  • the report may include a sample data section, which may provide information about the biological sample analyzed in the monitoring assessment, such as the source of biological sample obtained from the patient (e.g. blood, saliva, or type of tissue, etc.), how the sample was handled (e.g. storage temperature, preparatory protocols) and the date and time collected. Report fields with this information can generally be populated using data entered by the user, some of which may be provided as pre-scripted selections (e.g., using a drop-down menu).
  • the report may include a results section.
  • the report may include an assessment report section, which may include information generated after processing of the data as described herein.
  • the interpretive report can include a prediction of the likelihood that the subject will develop colon cancer.
  • the interpretive report can include a diagnosis of colon cancer.
  • the interpretive report can include a characterization of colon cancer.
  • the assessment portion of the report can optionally also include a recommendation(s). For example, where the results indicate that colon cancer is likely, the recommendation can include a recommendation that diet be altered and administered, etc., as recommended in the art.
  • the reports can include additional elements or modified elements.
  • the report can contain hyperlinks which point to internal or external databases which provide more detailed information about selected elements of the report.
  • the patient data element of the report can include a hyperlink to an electronic patient record, or a site for accessing such a patient record, which patient record is maintained in a confidential database. This latter embodiment may be of interest in an in-hospital system or in-clinic setting.
  • the report is recorded on a suitable physical medium, such as a computer readable medium, e.g., in a computer memory, zip drive, CD, DVD, etc.
  • the report can include all or some of the elements above, with the proviso that the report generally includes at least the elements sufficient to provide the analysis requested by the user (e.g. a calculated colon cancer marker level representation; a prediction, diagnosis or characterization of colon cancer).
  • reagents, systems and kits thereof for practicing one or more of the above-described methods.
  • the subject reagents, systems and kits thereof may vary greatly.
  • Reagents of interest include reagents specifically designed for use in producing the above- described marker level representations of colon cancer markers from a sample, for example, one or more detection elements, e.g. antibodies or peptides for the detection of protein, oligonucleotides for the detection of nucleic acids, etc.
  • the detection element comprises a reagent to detect the expression of a single colon cancer marker, for example, the detection element may be a dipstick, a plate, an array, or cocktail that comprises one or more detection elements, e.g. one or more antibodies, one or more oligonucleotides, one or more sets of PCR primers, etc. which may be used to detect the expression of one or more colon cancer marker simultaneously.
  • One type of reagent that is specifically tailored for generating marker level representations is a collection of antibodies that bind specifically to the protein markers, e.g. in an ELISA format, in a ECL format, in an xMAPTM microsphere format, on a proteomic array, in suspension for analysis by flow cytometry, by western blotting, by dot blotting, or by immunohistochemistry. Methods for using the same are well understood in the art.
  • These antibodies can be provided in solution. Alternatively, they may be provided pre-bound to a solid matrix, for example, the wells of a multi-well dish or the surfaces of xMAP microspheres.
  • Another type of such reagent is an array of probe nucleic acids in which the genes of interest are represented.
  • array formats are known in the art, with a wide variety of different probe structures, substrate compositions and attachment technologies (e.g., dot blot arrays, microarrays, etc.).
  • Representative array structures of interest include those described in U.S.
  • Another type of reagent that is specifically tailored for generating marker level representations of genes is a collection of gene specific primers that is designed to selectively amplify such genes (e.g., using a PCR-based technique, e.g., real-time RT-PCR).
  • Gene specific primers and methods for using the same are described in U.S. Patent No. 5,994,076, the disclosure of which is herein incorporated by reference.
  • probes, collections of primers, or collections of antibodies that include probes, primers or antibodies (also called reagents) that are specific for at least 1 gene/protein selected from the group consisting of CEA, DHEA.S, FERR, or a biochemical substrate specific for the cofactor/prosthetic group heme.
  • the collection of probes, primers, or antibodies includes reagents specific for CEA, DHEA.S, FERR, as well as a biochemical substrate specific for heme.
  • the subject probe, primer, or antibody collections or reagents may include reagents that are specific only for the genes/proteins/cofactors that are listed above, or they may include reagents specific for additional genes/proteins/cofactors that are not listed above, such as probes, primers, or antibodies specific for genes/proteins/cofactors whose expression pattern are known in the art to be associated with colon cancer genes, e.g. CEA/FERR, DHEA.S/FERR, and the geometric mean of the two ratios.
  • a system may be provided.
  • system refers to a collection of reagents, however compiled, e.g., by purchasing the collection of reagents from the same or different sources.
  • a kit may be provided.
  • kit refers to a collection of reagents provided, e.g., sold, together.
  • the nucleic acid- or antibody-based detection of the sample nucleic acid or protein, respectively may be coupled with an electrochemical biosensor platform that will allow multiplex determination of these biomarkers for personalized colon cancer genes care.
  • the systems and kits of the subject invention may include the abovedescribed arrays, gene-specific primer collections, or protein-specific antibody collections.
  • the systems and kits may further include one or more additional reagents employed in the various methods, such as primers for generating target nucleic acids, dNTPs and/or rNTPs, which may be either premixed or separate, one or more uniquely labeled dNTPs and/or rNTPs, such as biotinylated or Cy3 or Cy5 tagged dNTPs, gold or silver particles with different scattering spectra, or other post synthesis labeling reagent, such as chemically active derivatives of fluorescent dyes, enzymes, such as reverse transcriptases, DNA polymerases, RNA polymerases, and the like, various buffer mediums, e.g.
  • hybridization and washing buffers prefabricated probe arrays, labeled probe purification reagents and components, like spin columns, etc.
  • signal generation and detection reagents e.g. labeled secondary antibodies, streptavidin-alkaline phosphatase conjugate, chemifluorescent, chemiluminescent, electrochemiluminescenct substrate, and the like.
  • the subject systems and kits may also include one or more colon cancer genes phenotype determination elements, which element is, in many embodiments, a reference or control sample or marker representation that can be employed, e.g., by a suitable experimental or computing means, to make a colon cancer genes prognosis based on an "input" marker level profile, e.g., that has been determined with the above described marker determination element.
  • Representative colon cancer genes phenotype determination elements include samples from an individual known to have or not have colon cancer genes, databases of marker level representations, e.g., reference or control profiles or scores, and the like, as described above.
  • the subject kits will further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit.
  • One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc.
  • Yet another means would be a computer readable medium, e.g., diskette, CD, etc., on which the information has been recorded.
  • Yet another means that may be present is a website address which may be used via the internet to access the information at a removed site. Any convenient means may be present in the kits.
  • Example 1 As the fourth most common cancer worldwide, colon cancer claims over 1 million cases and 0.5 million causalities worldwide in 2018 (Bray et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 2018;86:394-424). Despite the prevalence and high mortality rate, colon cancer shows an optimistic prognostic outcome if reliable diagnosis is performed at early stage, with a 5-year relative survival rate over 90% for patients who are diagnosed at early stages (Lee et al. Stage-based variation in the effect of primary tumor side on all stages of colorectal cancer recurrence and survival. Clinical colorectal cancer 2018; 17:e569-e577; Feliciano et al.
  • colonoscopy is the gold standard for early diagnosis of colon cancer (Haseman et al. Failure of colonoscopy to detect colorectal cancer: evaluation of 47 cases in 20 hospitals. Gastrointestinal endoscopy 1997;45:451-455). With the guidance of colonoscope, small nonadvanced adenoma can even be removed during diagnosis (Atkin and Saunders. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002;51:v6-v9).
  • Plasma methylated septin 9 a colorectal cancer screening marker.
  • immunoassays are developed for the early diagnosis of colon cancer.
  • Cologuard was applied to detect colon cancer at different stages from feces of a 9989 cohort (Imperiale et al. Multitarget stool DNA testing for colorectal-cancer screening. New England Journal of Medicine 2014;370:1287-1297).
  • Cologuard managed to detect colon cancer from stage I to III with adequate sensitivity (61 ,5%-84.0%).
  • sensitivity of nonadvanced adenoma into account, such sensitivity became unsatisfactory. Therefore, novel molecular biomarkers are still highly sought to diagnose colon cancer at early stage.
  • PLoS computational biology 2010;6 in meta-analysis allowed us to identify consistent and significant differential gene expression across experiments to develop biomarkers for downstream experimental validation.
  • Serum proteins are routinely used to diagnose diseases, but sensitive and specific biomarkers are hard to find and may be due to their low serological abundance, which can easily be masked by highly abundant proteins.
  • Our serum protein marker discovery method (Ling et al. Plasma profiles in active systemic juvenile idiopathic arthritis: Biomarkers and biological implications. Proteomics 2010) combines antibody-based serum abundant protein depletion and 2D gel comparative profiling to discover differential protein gel spots between colon cancer, nonadvanced adenoma and control sera for subsequent protein mass spectrometric identification.
  • ECL electrochemiluminescence
  • biomarker panel score was defined as the ratio between two protein biomarkers in the blood.
  • a composite panel combining CEA, DHEA.S, and FERR was derived as colon cancer classification panel where the score was calculated as the ratio of CEA to FERR, the ratio of DHEA.S to FERR, or the geometric of the two ratios.
  • biomarker candidates from expression meta-analysis and 2D gel profiling, were validated with available serum assays using cancer (colon cancer), tumor (nonadvanced adenoma), and control samples.
  • cancer colon cancer
  • tumor nonadvanced adenoma
  • control samples Detailed with whisker box and scatter plots in Figures 2-6, CEA, FERR, CEA/FERR, DHEA.S/FERR and the geometric mean of the two ratios were validated by ECL assays (Mann-Whitney U-test).
  • Table 2 shows the sensitivity and specificity of the three optimal bio-markers: CEA/FERR, DHEA.S/FERR and the geometric mean of the two ratios.

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Abstract

L'invention concerne des procédés pour fournir une évaluation du cancer du côlon à l'aide de biomarqueurs protéiques mesurés à partir d'échantillons de sang, et des compositions des biomarqueurs protéiques. L'invention concerne également des systèmes, des dispositifs et des kits pour la mise en oeuvre des procédés. Ces compositions et procédés sont applicables au diagnostic, au pronostic, à l'administration et aux traitements pour un sujet atteint d'un cancer du côlon.
PCT/IB2019/000896 2019-08-02 2019-08-02 Procédés et compositions pour fournir une évaluation du cancer du côlon à l'aide de biomarqueurs protéiques WO2021024009A1 (fr)

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US20100240068A1 (en) * 2007-12-10 2010-09-23 Johann Karl Marker panel for colorectal cancer
WO2011027310A1 (fr) * 2009-09-03 2011-03-10 Koninklijke Philips Electronics N.V. Nouveaux marqueurs tumoraux
CN106546744A (zh) * 2015-09-17 2017-03-29 上海透景生命科技股份有限公司 通过粪便血红蛋白、转铁蛋白和pkm2联合检测评定结肠直肠癌的方法及相应试剂盒
CN107110865A (zh) * 2014-08-22 2017-08-29 雅培制药有限公司 用于结肠直肠癌的早期检测的方法
CN106093388B (zh) * 2010-12-14 2018-12-11 吉安特科技股份有限公司 抗cxcl16 抗体和抗cxcr6 抗体在治疗或检测癌症中的用途
CN109791154A (zh) * 2016-07-25 2019-05-21 比利时意志有限责任公司 结肠直肠癌的组合测试

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100240068A1 (en) * 2007-12-10 2010-09-23 Johann Karl Marker panel for colorectal cancer
WO2011027310A1 (fr) * 2009-09-03 2011-03-10 Koninklijke Philips Electronics N.V. Nouveaux marqueurs tumoraux
CN106093388B (zh) * 2010-12-14 2018-12-11 吉安特科技股份有限公司 抗cxcl16 抗体和抗cxcr6 抗体在治疗或检测癌症中的用途
CN107110865A (zh) * 2014-08-22 2017-08-29 雅培制药有限公司 用于结肠直肠癌的早期检测的方法
CN106546744A (zh) * 2015-09-17 2017-03-29 上海透景生命科技股份有限公司 通过粪便血红蛋白、转铁蛋白和pkm2联合检测评定结肠直肠癌的方法及相应试剂盒
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