Markers for endometrial cancer

Abstract

The invention relates to the surprising finding that biomarkers corresponding to ACAA1, AP1M2, CGN, DDR1, EPS8L2, FASTKD1, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPFIBP2, PPP1R16A, RASSF7, RNF183, SIRT6, TJP3, EFEMP2, SOCS2, and DCN are differentially expressed in control samples as compared to samples from patients having endometrial cancer and are therefore useful for detecting endometrial cancer. In particular these biomarkers having excellent sensitivity, specificity, and/or the ability to separate affected from non affected individuals. Furthermore, the inventors found that the differential expression of these biomarkers in primary endometrial cancer tumor tissue is correlated to their expression level in uterine fluid samples as compared to control values. Thus these biomarkers are robust in that they are found to be differentially expressed in several different types of samples from affected and individuals.

1 . An in vitro method of diagnosing endometrial cancer in a patient comprising: detecting the level of the biomarker IKBKE in a sample from the patient, wherein an increased level of the biomarker IKBKE compared to a control value indicates the existence of endometrial cancer in the patient. 
     
     
         2 . The in vitro method of  claim 1 , further comprising detecting the level of one or more biomarkers selected from the group consisting of GMIP, EFEMP2, and P4HB. 
     
     
         3 . The in vitro method of  claim 1 , further comprising detecting the level of one or more biomarkers selected from the group consisting DDR1, FASTKD1, SIRT6 and PHKG2. 
     
     
         4 . The in vitro method of  claim 1 , further comprising detecting the level of from one or more biomarkers selected from the group consisting of ACAA1, AP1M2, EPS8L2, P2RX4, PPFIBP2, PPP1R16A, CGN, RASSF7, RNF183, TJP3, SOCS2, and DCN. 
     
     
         5 . The in vitro method of  claim 1 , wherein said patient has a risk factor for endometrial cancer or is being screened for endometrial cancer. 
     
     
         6 . The in vitro method of  claim 1 , wherein said sample from said patient is from a patient with abnormal uterine bleeding. 
     
     
         7 . The in vitro method of  claim 1 , wherein said sample from said patient is from a patient having an endometrium with increased thickness. 
     
     
         8 . The in vitro method of  claim 1 , wherein said sample is from a pre-menopausal or post-menopausal patient. 
     
     
         9 . The in vitro method of  claim 1 , wherein said sample is from a peri-menopausal patient. 
     
     
         10 . The in vitro method of  claim 1 , wherein said sample is chosen from a tissue sample, blood and/or serum, and uterine fluid. 
     
     
         11 . The in vitro method of  claim 10 , wherein said sample is a uterine fluid sample. 
     
     
         12 . The in vitro method of  claim 1 , wherein the level of the biomarker(s) is determined by RT-PCR. 
     
     
         13 . The in vitro method of  1 , wherein the number of biomarkers detected is between 2 to 20. 
     
     
         14 . The in vitro method of  claim 1 , wherein one or more additional biomarkers are detected. 
     
     
         15 . The in vitro method of  claim 14 , wherein said one or more additional biomarkers are chosen from differential diagnosis biomarkers, prognostic biomarkers, biomarkers useful for detecting endometrial cancer, biomarkers for classifying endometrial cancer and auxiliary biomarkers for detecting endometrial cancer. 
     
     
         16 . The in vitro method of  claim 1 , comprising determining the level of the biomarker IKBKE in a uterine fluid aspirate sample from a patient having a symptom or risk factor for endometrial cancer, wherein the biomarker IKBKE is differentially expressed in endometrial cancer as compared to control values representative of individuals not affected by endometrial cancer, wherein if the levels of the biomarker IKBKE is upregulated in the endometrial aspirate sample from the patient then the patient has an increased likelihood of having endometrial cancer. 
     
     
         17 . The in vitro method of  claim 1 , comprising determining the level of RNA expression of the biomarker IKBKE by quantitative PCR in a uterine fluid sample from a human patient having a symptom or risk factor for endometrial cancer, wherein an increased level of the biomarker IKBKE as compared to control indicates the existence of endometrial cancer. 
     
     
         18 . The in vitro method of  claim 1 , wherein P4HB and IKBKE are detected. 
     
     
         19 . The in vitro method of  claim 1 , wherein EFEMP2 and IKBKE are detected. 
     
     
         20 . The in vitro method of  claim 1 , wherein P4HB, GMIP, and IKBKE are detected. 
     
     
         21 . The in vitro method of  claim 1 , wherein a combination of markers is detected, wherein said combination is selected from the group consisting of IKBKE and P4HB; IKBKE and SOCS2; GMIP and IKBKE; GMIP, SOCS2, and IKBKE; GMIP, IKBKE, and P4HB; IKBKE, P4HB, and SOCS2; GMIP, IKBKE, P4HB, and SOCS2; GMIP, SOCS2, IKBKE, and EPS8L2; GMIP, IKBKE, P4HB, and EPS8L2; IKBKE, P4HB, SOCS2, and EPS8L2; GMIP, IKBKE, P4HB, SOCS2, and DDR1; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, and PPP1R16A; GMIP, IKBKE, P4HB, SOCS2, PHKG2, and RASSF7; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, and DDR1; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, PPP1R16A, and DDR1; DDR1, EPS8L2, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPP1R16A, RASSF7, SIRT6, TJP3, and SOCS2; and DDR1, EPS8L2, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPP1R16A, RASSF7, SIRT6, TJP3, RNF183 and SOCS2; or
 wherein said combination comprises GMIP, IKBKE, P4HB, SOCS2 and FASTKD1; GMIP, IKBKE, P4HB, SOCS2 and DDR1; GMIP, IKBKE, P4HB, SOCS2 and PHKG2; GMIP, IKBKE, P4HB, SOCS2 and SIRT6; GMIP, IKBKE, P4HB, SOCS2 and ACAA1; GMIP, IKBKE, P4HB, SOCS2 and EFEMP2; GMIP, IKBKE, P4HB, SOCS2 and EPS8L2; GMIP, IKBKE, P4HB, SOCS2 and P2RX4; GMIP, IKBKE, P4HB, SOCS2 and PPFIBP2; GMIP, IKBKE, P4HB, SOCS2 and PPP1R16A; GMIP, IKBKE, P4HB, SOCS2, ACAA1 and FASTKD1; GMIP, IKBKE, P4HB, SOCS2, PHKG2 and FASTKD1; GMIP, IKBKE, P4HB, SOCS2, SIRT6 and FASTKD1; ACAA1, AP1M2, EPS8L2, IKBKE, P2RX4, P4HB, PPFIBP2, PPP1R16A, SIRT6, and EFEMP2; GMIP, IKBKE, P4HB, and EFEMP2; DDR1, FASTKD1, PHKG2, SIRT6, SOCS2, GMIP, IKBKE, P4HB, and EFEMP2; DDR1, FASTKD1, PHKG2, SIRT6, GMIP, IKBKE, P4HB, and EFEMP2; or P4HB, EFEMP2, IKBKE, GMIP, and FASTKD1; or   wherein said combination comprises GMIP, IKBKE, P4HB, EFEMP2 and FASTKD1; GMIP, IKBKE, P4HB, EFEMP2 and DDR1; GMIP, IKBKE, P4HB, EFEMP2 and PHKG2; GMIP, IKBKE, P4HB, EFEMP2 and SIRT6; GMIP, IKBKE, P4HB, EFEMP2 and ACAA1; GMIP, IKBKE, P4HB, SOCS2 and EFEMP2; GMIP, IKBKE, P4HB, EFEMP2 and EPS8L2; GMIP, IKBKE, P4HB, EFEMP2 and P2RX4; GMIP, IKBKE, P4HB, EFEMP2 and PPFIBP2; GMIP, IKBKE, P4HB, EFEMP2 and PPP1R16A; GMIP, IKBKE, P4HB, EFEMP2, ACAA1 and FASTKD1; GMIP, IKBKE, P4HB, EFEMP2, PHKG2 and FASTKD1; or GMIP, IKBKE, P4HB, EFEMP2, SIRT6 and FASTKD1.   
     
     
         22 . The in vitro method of  claim 1 , comprising
 (a) providing a uterine fluid sample obtained from a patient with a pipelle device or syringe wherein the patient has a risk factor or symptom of endometrial cancer; contacting said sample with an agent capable of preserving, preventing, or lessening the degradation of RNA in said uterine fluid sample;   (b) determining in said sample the expression level of mRNA corresponding to the marker IKBKE and one or more endogenous genes using quantitative PCR; normalizing the expression level of the biomarker IKBKE with the one or more endogenous genes; and   (c) comparing the normalized level of the biomarker IKBKE to a control value wherein differential expression of the biomarker IKBKE indicates endometrial cancer or an increased likelihood of endometrial cancer.   
     
     
         23 . The in vitro method of  claim 22 , wherein said one or more endogenous genes are selected from the group consisting of POLR2A, B2M, PFN1, HMBS, G6PD, and PABPN1. 
     
     
         24 . The in vitro method of  claim 1 , wherein the level of the biomarker IKBKE is the mRNA level. 
     
     
         25 . The in vitro method of  claim 1 , wherein the detecting step is performed using a nucleic acid encoding IKBKE. 
     
     
         26 . The in vitro method of  claim 1 , wherein nucleic acid encoding IKBKE is selected from the group consisting of IKBKE mRNA, IKBKE cDNA, or a complement thereof. 
     
     
         27 . The in vitro method of  claim 1 , wherein the detecting step is performed using a nucleic acid encoding one or more primers that are specific to IKBKE.