Detecting cancer cell of origin

Abstract

Methods and compositions are provided for determining a pan-cancer clustering of cluster assignment (COCA) subtype of a cancer in an individual by detecting the expression level of at least one classifier biomarker selected from a group of classifier biomarkers for COCA subtypes. Also provided herein are methods and compositions for determining the response of an individual with a COCA subtype to a therapy such as immunotherapy.

What is claimed is: 
     
         1 . A method for determining a clustering of cluster assignments (COCA) subtype of a tumor cancer sample obtained from a patient, the method comprising detecting an expression level of at least one classifier biomarker of Table 1, wherein the detection of the expression level of the classifier biomarker specifically identifies a C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28 COCA subtype. 
     
     
         2 . The method of  claim 1 , wherein the method further comprises comparing the detected levels of expression of the at least one classifier biomarker of Table 1 to the expression of the at least one classifier biomarker of Table 1 in at least one sample training set(s), wherein the at least one sample training set(s) comprises expression data of the at least one classifier biomarker of Table 1 from a reference C1 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C2 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C3 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C4 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C6 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C8 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C9 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C10 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C12 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C14 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C15 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C16 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C17 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C19 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C20 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C21 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C22 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C24 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C25 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C26 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C28 sample or a combination thereof; and classifying the sample as the C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28 COCA subtype based on the results of the comparing step. 
     
     
         3 . The method of  claim 2 , wherein the comparing step comprises applying a statistical algorithm which comprises determining a correlation between the expression data obtained from the sample and the expression data from the at least one training set(s); and classifying the sample as a C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28 COCA subtype based on the results of the statistical algorithm. 
     
     
         4 . The method of  claim 1 , wherein the C1 COCA subtype indicates that a tumor sample is substantially similar to or is adenocortical carcinoma; the C2 COCA subtype indicates that a tumor sample is substantially similar to or is glioblastoma; the C3 COCA subtype indicates that a tumor sample is substantially similar to or is an ovarian serous cystadenocarcinoma (epithelial ovarian cancer); the C4 COCA subtype indicates that a tumor sample is substantially similar to or is squamous cell carcinoma of the lung, the head and neck or the bladder; the C6 COCA subtype indicates that a tumor sample is substantially similar to or is lung adenocarcinoma; the C8 COCA subtype indicates that a tumor sample is substantially similar to or is pancreatic adenocarcinoma; the C9 COCA subtype indicates that a tumor sample is substantially similar to or is uterine carcinosarcoma; the C10 COCA subtype indicates that a tumor sample is substantially similar to or is the basal subtype of breast cancer; the C12 COCA subtype indicates that a tumor sample is substantially similar to or is uterine corpus endometrial cancer; the C14 COCA subtype indicates that a tumor sample is substantially similar to or is prostate cancer; the C15 COCA subtype can indicate that a tumor sample is substantially similar to or is non-squamous cervical cancer; the C16 COCA subtype indicates that a tumor sample is substantially similar to or is a bladder urothelial carcinoma; the C17 COCA subtype indicates that a tumor sample is substantially similar to or is a testicular germ cell tumor; the C19 COCA subtype indicates that a tumor sample is substantially similar to or is a colon, rectal, esophageal or stomach adenocarcinoma; the C20 COCA subtype indicates that a tumor sample is substantially similar to or is a sarcoma; the C21 COCA subtype indicates that a tumor sample is substantially similar to or is a kidney chromophobe, kidney renal papillary cell carcinoma or kidney renal clear cell carcinoma; the C22 COCA subtype indicates that a tumor sample is substantially similar to or is liver hepatocellular carcinoma; the C24 COCA subtype indicates that a tumor sample is substantially similar to or is the luminal subtype of breast cancer; the C25 COCA subtype indicates that a tumor sample is substantially similar to or is thymoma; the C26 COCA subtype indicates that a tumor sample is substantially similar to or is melanoma; or the C28 COCA subtype indicates that a tumor sample is substantially similar to or is thyroid cancer. 
     
     
         5 . The method of  claim 1 , wherein the expression level of the classifier biomarker is detected at the nucleic acid level. 
     
     
         6 . The method of  claim 5 , wherein the nucleic acid level is RNA or cDNA. 
     
     
         7 . The method  claim 5  or  6 , wherein the detecting an expression level comprises performing quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR), RNAseq, microarrays, gene chips, nCounter Gene Expression Assay, Serial Analysis of Gene Expression (SAGE), Rapid Analysis of Gene Expression (RAGE), nuclease protection assays, Northern blotting, or any other equivalent gene expression detection techniques. 
     
     
         8 . The method of  claim 7 , wherein the expression level is detected by performing RNAseq. 
     
     
         9 . The method of  claim 8 , wherein the detection of the expression level comprises using at least one pair of oligonucleotide primers specific for at least one classifier biomarker of Table 1. 
     
     
         10 . The method of  claim 1 , wherein the sample is a formalin-fixed, paraffin-embedded (FFPE) tissue sample, a fresh or a frozen tissue sample, an exosome, wash fluids, cell pellets, or a bodily fluid obtained from the patient. 
     
     
         11 . The method of  claim 10 , wherein the bodily fluid is blood or fractions thereof, urine, saliva, or sputum. 
     
     
         12 . The method of  claim 1 , wherein the at least one classifier biomarker comprises a plurality of classifier biomarkers. 
     
     
         13 . The method of  claim 12 , wherein the plurality of classifier biomarkers comprises, consists essentially of or consists of at least 2 classifier biomarkers, at least 4 classifier biomarkers, at least 6 classifier biomarkers, at least 8 classifier biomarkers, at least 10 classifier biomarkers, at least 12 classifier biomarkers, at least 14 classifier biomarkers, at least 16 classifier biomarkers, at least 18 classifier biomarkers, at least 20 classifier biomarkers, at least 30 classifier biomarkers, at least 40 classifier biomarkers, at least 50 classifier biomarkers, at least 60 classifier biomarkers, at least 70 classifier biomarkers or at least 80 classifier biomarkers of Table 1. 
     
     
         14 . The method of  claim 1 , wherein the at least one classifier biomarker comprises, consists essentially of or consists of all the classifier biomarkers of Table 1. 
     
     
         15 . A method of detecting a biomarker in a tumor sample obtained from a patient, the method comprising measuring the expression level of a plurality of classifier biomarker nucleic acids selected from Table 1 using an amplification, hybridization and/or sequencing assay. 
     
     
         16 . The method of  claim 15 , wherein the patient is suffering from or is suspected of suffering from kidney renal papillary cell carcinoma (KIRP); breast invasive carcinoma (BRCA); thyroid cancer (THCA); bladder urothelial carcinoma (BLCA); prostate adenocarcinoma (PRAD); kidney chromophobe (KICH); cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC); kidney renal clear cell carcinoma (KIRC); liver hepatocellular carcinoma (LIHC); low grade glioma (LGG); sarcoma (SARC); lung adenocarcinoma (LUAD); colon adenocarcinoma (COAD); head and neck squamous cell carcinoma (HNSC); uterine corpus endometrial carcinoma (UCEC); glioblastoma multiforme (GBM); esophageal carcinoma (ESCA); stomach adenocarcinoma (STAD); ovarian serous cystadenocarcinoma (OV); rectum adenocarcinoma (READ); adrenocortical carcinoma (ACC); uveal melanoma (UVM); mesothelioma (MESO); pheochromocytoma and paraganglioma (PCPG); skin cutaneous melanoma (SKCM); uterine carcinsarcoma (UCS); lung squamous cell carcinoma (LUSC); testicular germ cell tumors (TGCT); cholangiocarcinoma (CHOL); pancreatic adenocarcinoma (PAAD); thymoma (THYM); or Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC). 
     
     
         17 . The method of  claim 15  or  16 , wherein the amplification, hybridization and/or sequencing assay comprises performing quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR), RNAseq, microarrays, gene chips, nCounter Gene Expression Assay, Serial Analysis of Gene Expression (SAGE), Rapid Analysis of Gene Expression (RAGE), nuclease protection assays, Northern blotting, or any other equivalent gene expression detection techniques. 
     
     
         18 . The method of  claim 17 , wherein the expression level is detected by performing RNAseq. 
     
     
         19 . The method of  claim 18 , wherein the detection of the expression level comprises using at least one pair of oligonucleotide primers per each of the plurality of biomarker nucleic acids selected from Table 1. 
     
     
         20 . The method of  claim 15 , wherein the sample is a formalin-fixed, paraffin-embedded (FFPE) tissue sample, fresh or a frozen tissue sample, an exosome, wash fluids, cell pellets, or a bodily fluid obtained from the patient. 
     
     
         21 . The method of  claim 20 , wherein the bodily fluid is blood or fractions thereof, urine, saliva, or sputum. 
     
     
         22 . The method of  claim 15 , wherein the plurality of classifier biomarkers comprises, consists essentially of or consists of at least 2 classifier biomarkers, at least 5 classifier biomarkers, at least 10 classifier biomarkers, at least 20 classifier biomarkers, at least 30 classifier biomarkers, at least 40 classifier biomarkers, at least 50 classifier biomarkers, at least 60 classifier biomarkers, at least 70 classifier biomarkers or at least 80 classifier biomarkers of Table 1. 
     
     
         23 . The method of  claim 15 , wherein the plurality of biomarker nucleic acids comprises, consists essentially of or consists of all the classifier biomarker nucleic acids of Table 1. 
     
     
         24 . A method of treating cancer in a subject, the method comprising:
 measuring the expression level of at least one biomarker nucleic acid in a tumor sample obtained from the subject, wherein the at least one biomarker nucleic acid is selected from a set of biomarkers listed in Table 1, wherein the presence, absence and/or level of the at least one biomarker indicates a COCA subtype of the cancer; and administering a therapeutic agent based on the COCA subtype of the cancer.   
     
     
         25 . The method of  claim 24 , wherein the at least one biomarker nucleic acid selected from the set of biomarkers comprises, consists essentially of or consists of at least 2 classifier biomarkers, at least 5 classifier biomarkers, at least 10 classifier biomarkers, at least 20 classifier biomarkers, at least 30 classifier biomarkers, at least 40 classifier biomarkers, at least 50 classifier biomarkers, at least 60 classifier biomarkers, at least 70 classifier biomarkers or at least 80 classifier biomarkers of Table 1. 
     
     
         26 . The method of  claim 24  or  25 , further comprising measuring the expression of at least one biomarker from an additional set of biomarkers. 
     
     
         27 . The method of  claim 26 , wherein the additional set of biomarkers comprises at least an immune cell signature, a cell proliferation signature, or drug target genes. 
     
     
         28 . The method of  claim 24 , wherein the measuring the expression level is conducted using an amplification, hybridization and/or sequencing assay. 
     
     
         29 . The method of  claim 28 , wherein the amplification, hybridization and/or sequencing assay comprises performing quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR), RNAseq, microarrays, gene chips, nCounter Gene Expression Assay, Serial Analysis of Gene Expression (SAGE), Rapid Analysis of Gene Expression (RAGE), nuclease protection assays, Northern blotting, or any other equivalent gene expression detection techniques. 
     
     
         30 . The method of  claim 29 , wherein the expression level is detected by performing RNAseq. 
     
     
         31 . The method of  claim 24 , wherein the sample is a formalin-fixed, paraffin-embedded (FFPE) tissue sample, fresh or a frozen tissue sample, an exosome, wash fluids, cell pellets, or a bodily fluid obtained from the patient. 
     
     
         32 . The method of  claim 31 , wherein the bodily fluid is blood or fractions thereof, urine, saliva, or sputum. 
     
     
         33 . The method of  claim 24 , wherein the subject's COCA subtype is selected from C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28. 
     
     
         34 . The method of  claim 33 , wherein the C1 COCA subtype indicates that a tumor sample is substantially similar to or is adenocortical carcinoma; the C2 COCA subtype indicates that a tumor sample is substantially similar to or is glioblastoma; the C3 COCA subtype indicates that a tumor sample is substantially similar to or is an ovarian serous cystadenocarcinoma (epithelial ovarian cancer); the C4 COCA subtype indicates that a tumor sample is substantially similar to or is squamous cell carcinoma of the lung, the head and neck or the bladder; the C6 COCA subtype indicates that a tumor sample is substantially similar to or is lung adenocarcinoma; the C8 COCA subtype indicates that a tumor sample is substantially similar to or is pancreatic adenocarcinoma; the C9 COCA subtype indicates that a tumor sample is substantially similar to or is uterine carcinosarcoma; the C10 COCA subtype indicates that a tumor sample is substantially similar to or is the basal subtype of breast cancer; the C12 COCA subtype indicates that a tumor sample is substantially similar to or is uterine corpus endometrial cancer; the C14 COCA subtype indicates that a tumor sample is substantially similar to or is prostate cancer; the C15 COCA subtype can indicate that a tumor sample is substantially similar to or is non-squamous cervical cancer; the C16 COCA subtype indicates that a tumor sample is substantially similar to or is a bladder urothelial carcinoma; the C17 COCA subtype indicates that a tumor sample is substantially similar to or is a testicular germ cell tumor; the C19 COCA subtype indicates that a tumor sample is substantially similar to or is a colon, rectal, esophageal or stomach adenocarcinoma; the C20 COCA subtype indicates that a tumor sample is substantially similar to or is a sarcoma; the C21 COCA subtype indicates that a tumor sample is substantially similar to or is a kidney chromophobe, kidney renal papillary cell carcinoma or kidney renal clear cell carcinoma; the C22 COCA subtype indicates that a tumor sample is substantially similar to or is liver hepatocellular carcinoma; the C24 COCA subtype indicates that a tumor sample is substantially similar to or is the luminal subtype of breast cancer; the C25 COCA subtype indicates that a tumor sample is substantially similar to or is thymoma; the C26 COCA subtype indicates that a tumor sample is substantially similar to or is melanoma; or the C28 COCA subtype indicates that a tumor sample is substantially similar to or is thyroid cancer. 
     
     
         35 . A method of predicting overall survival in a cancer patient, the method comprising detecting an expression level of at least one classifier biomarker of Table 1 in a tumor sample obtained from a patient, wherein the detection of the expression level of the at least one classifier biomarker specifically identifies a COCA subtype, and wherein identification of the COCA subtype is predictive of the overall survival in the patient. 
     
     
         36 . The method of  claim 35 , wherein the method further comprises comparing the detected levels of expression of the at least one classifier biomarker of Table 1 to the expression of the at least one classifier biomarker of Table 1 in at least one sample training set(s), wherein the at least one sample training set(s) comprises expression data of the at least one classifier biomarker of Table 1 from a reference C1 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C2 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C3 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C4 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C6 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C8 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C9 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C10 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C12 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C14 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C15 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C16 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C17 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C19 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C20 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C21 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C22 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C24 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C25 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C26 sample, expression data of the at least one classifier biomarker of Table 1 from a reference C28 sample or a combination thereof; and classifying the sample as the C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28 COCA subtype based on the results of the comparing step. 
     
     
         37 . The method of  claim 36 , wherein the comparing step comprises applying a statistical algorithm which comprises determining a correlation between the expression data obtained from the sample and the expression data from the at least one training set(s); and classifying the sample as a C1, C2, C3, C4, C6, C8, C9, C10, C12, C14, C15, C16, C17, C19, C20, C21, C22, C24, C25, C26 or C28 COCA subtype based on the results of the statistical algorithm. 
     
     
         38 . The method of any one of the  claims 35 - 37 , wherein the expression level of the classifier biomarker is detected at the nucleic acid level. 
     
     
         39 . The method of  claim 38 , wherein the nucleic acid level is RNA or cDNA. 
     
     
         40 . The method of  claim 35 , wherein the detecting an expression level comprises performing quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR), RNAseq, microarrays, gene chips, nCounter Gene Expression Assay, Serial Analysis of Gene Expression (SAGE), Rapid Analysis of Gene Expression (RAGE), nuclease protection assays, Northern blotting, or any other equivalent gene expression detection techniques. 
     
     
         41 . The method of  claim 40 , wherein the expression level is detected by performing RNAseq. 
     
     
         42 . The method of  claim 35 , wherein the detection of the expression level comprises using at least one pair of oligonucleotide primers specific for at least one classifier biomarker of Table 1. 
     
     
         43 . The method of  claim 35 , wherein the sample is a formalin-fixed, paraffin-embedded (FFPE) tissue sample, fresh or a frozen tissue sample, an exosome, wash fluids, cell pellets, or a bodily fluid obtained from the patient. 
     
     
         44 . The method of  claim 43 , wherein the bodily fluid is blood or fractions thereof, urine, saliva, or sputum. 
     
     
         45 . The method of  claim 35 , wherein the at least one classifier biomarker comprises a plurality of classifier biomarkers. 
     
     
         46 . The method of  claim 45 , wherein the plurality of classifier biomarkers comprises, consists essentially of or consists of at least 2 classifier biomarkers, at least 5 classifier biomarkers, at least 10 classifier biomarkers, at least 20 classifier biomarkers, at least 30 classifier biomarkers, at least 40 classifier biomarkers, at least 50 classifier biomarkers, at least 60 classifier biomarkers, at least 70 classifier biomarkers or at least 80 classifier biomarkers of Table 1. 
     
     
         47 . The method of  claim 35 , wherein the at least one classifier biomarker comprises, consists essentially of or consists of all the classifier biomarkers of Table 1.