Diagnotic markers

Abstract

The present invention provides methods of predicting response to a cancer therapy based on the methylation status of the ERBB2 gene. One aspect of the invention provides a method of predicting response to an EGFR inhibitor therapy based on the methylation status of the ERBB2 gene.

What is claimed is: 
     
         1 . A method of determining the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising detecting the methylation status of the ERBB2 gene in a sample tumor cell, wherein hypomethylation of the ERBB2 gene indicates that the tumor cell growth is sensitive to inhibition with the EGFR inhibitor. 
     
     
         2 . A method of identifying a cancer patient who is likely to benefit from treatment with an EFGR inhibitor comprising detecting the methylation status of the ERBB2 gene from a sample from the patient's cancer, wherein the patient is identified as being likely to benefit from treatment with the EGFR inhibitor if the methylation status of the ERBB2 gene is detected to be hypomethylation. 
     
     
         3 . The method of  claim 1 , wherein the methylation status is detected in a part of the ERBB2 gene. 
     
     
         4 . The method of  claim 3 , wherein the part of the ERBB2 gene is an enhancer. 
     
     
         5 . The method of  claim 3 , wherein the part of the ERBB2 gene is an enhancer and a promoter. 
     
     
         6 . The method of  claim 3 , wherein the part of the ERBB2 gene comprises a 6 CpG repeat region. 
     
     
         7 . The method of  claim 3 , wherein the part of the ERBB2 gene comprises the nucleic acid sequence of SEQ ID NO:1. 
     
     
         8 . The method of  claim 6 , wherein the part of the ERBB2 gene comprises the nucleic acid sequence of SEQ ID NO: 2. 
     
     
         9 . The method of  claim 1 , wherein hypomethylation is indicated by less than about 50% methylation of the ERBB2 gene. 
     
     
         10 . The method of  claim 9 , where hypomethylation is indicated by less than about 20% methylation of the ERBB2 gene. 
     
     
         11 . The method of  claim 3 , wherein hypomethylation is indicated by less than about 50% methylation of the part of the ERBB2 gene. 
     
     
         12 . The method of  claim 11 , wherein hypomethylation is indicated by less than about 20% methylation of the part of the ERBB2 gene. 
     
     
         13 . The method of  claim 2 , further comprising administering to the patient a therapeutically effective amount of an EGFR inhibitor if the patient is identified as one who will likely benefit from treatment with the EGFR inhibitor. 
     
     
         14 . A method of treating a cancer in a patient comprising administering a therapeutically effective amount of an EGFR inhibitor to the patient, wherein the patient, prior to administration of the EGFR inhibitor, was diagnosed with a cancer which exhibits hypomethylation of the ERBB2 gene, wherein the hypomethylation of the ERBB2 gene is indicative of therapeutic responsiveness by the subject to the EGFR inhibitor. 
     
     
         15 . A method of selecting a therapy for a cancer patient, comprising
 a. detecting the methylation status of the ERBB2 gene from a sample from the patient's cancer, and   b. selecting an EGFR inhibitor for the therapy when the ERBB2 gene is detected to be hypomethylated.   
     
     
         16 . The method of  claim 15 , further comprising administering to the patient a therapeutically effective amount of the EGFR inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the EGFR inhibitor is erlotinib, cetuximab, or panitumumab. 
     
     
         18 . A method of determining overexpression of ERBB2 gene in a cell comprising detecting the methylation status of the ERBB2 gene in the cell, wherein ERBB2 gene hypomethylation indicates overexpression of ERBB2 in the cell. 
     
     
         19 . A method of treating a cancer in a patient comprising administering a therapeutically effective amount of a HER2 inhibitor to the patient, wherein the patient, prior to administration of the HER2 inhibitor, was diagnosed with a cancer which exhibits hypomethylation of the ERBB2 gene, wherein the hypomethylation of the ERBB2 gene is indicative of therapeutic responsiveness by the subject to the HER2 inhibitor. 
     
     
         20 . The method of  claim 1 , wherein the methylation status is detected by pyrosequencing. 
     
     
         21 . The method of  claim 1 , wherein the ERBB2 gene is from a formalin-fixed paraffin embedded (FFPE) tissue or from fresh frozen tissue. 
     
     
         22 . The method of  claim 21 , wherein the ERBB2 gene isolated from the tissue sample is preamplified before pyrosequencing.