Socs-3 promoter methylation in cancer

Abstract

This invention provides compositions and methods for the diagnosis and treatment of cancers that exhibit decreased SOCS-3 expression.

1 . A method of detecting cancer in a patient, the method comprising: 
 determining the level of a transcript encoding SEQ ID NO:2 in a biological sample from the patient; and    detecting a decrease in the level of the transcript relative to normal, thereby detecting the presence of cancer in the patient.    
     
     
         2 . The method of  claim 1 , wherein the cancer is selected from a group consisting of lung cancer, breast cancer, mesothelioma, colon cancer, and sarcoma.  
     
     
         3 . The method of  claim 1 , wherein the step of determining the level of the transcript comprises an amplification reaction.  
     
     
         4 . A method of detecting cancer in a patient, the method comprising: 
 determining the level of a polypeptide having the sequence set forth in SEQ ID NO:2 in a biological sample from the patient: and    detecting an increase in the level of the polypeptide relative to normal, thereby detecting the presence of cancer in the patient.    
     
     
         5 . The method of  claim 4 , wherein the cancer is selected from the group consisting of lung cancer, breast cancer, mesothelioma, colon cancer, and sarcoma.  
     
     
         6 . The method of  claim 4 , wherein the step of determining the level of the polypeptide comprises performing an immunoassay.  
     
     
         7 . A method of detecting cancer in a patient, the method comprising: 
 determining the amount of methylation of a SOCS-3 promoter in a biological sample from the patient; and    detecting an increase in the amount of methylation of the sample relative to normal, thereby detecting the presence of cancer in the patient.    
     
     
         8 . The method of  claim 7 , wherein the amount of methylation of the CpG residues that occur within the region from -1005 to -983 or from -754 to -737 of SEQ ID NO:3 is determined.  
     
     
         9 . The method of  claim 7 , wherein the amount of methylation of the SOCS-3 promoter is determined using bisulfite sequencing.  
     
     
         10 . The method of  claim 7 , wherein the amount of methylation of the SOCS-3 promoter is determined using methylation-specific PCR.  
     
     
         11 . The method of  claim 7 , wherein the amount of methylation is detected using a methylation-sensitive restriction enzyme.  
     
     
         12 . A method of monitoring the efficacy of a therapeutic treatment of cancer, the method comprising the steps of: 
 (i) providing a biological sample from a patient undergoing the therapeutic treatment; and    (ii) detecting the level of: a polypeptide having an amino acid sequence of SEQ ID NO:2, or of a nucleic acid that encodes the polypeptide, in the biological sample compared to a level in a biological sample from the patient prior to, or earlier in, the therapeutic treatment, thereby monitoring the efficacy of the therapy.    
     
     
         13 . A method of monitoring the efficacy of a therapeutic treatment of cancer, the method comprising the steps of: 
 (i) providing a biological sample from a patient undergoing the therapeutic treatment; and    (ii) detecting the level of methylation of the SOCS-3 promoter in the biological sample compared to a level in a biological sample from the patient prior to, or earlier in, the therapeutic treatment, thereby monitoring the efficacy of the therapy.    
     
     
         14 . A method of screening for an agent that increases SOCS-3 activity, the method comprising incubating a test compound with a cell comprising a SOCS-3 nucleic acid having at least 80% identity to SEQ ID NO:1; 
 selecting a compound that increases SOCS-3 activity, thereby identifying an agent that increases SOCS-3 activity.    
     
     
         15 . The method of  claim 14 , wherein the SOCS-3 nucleic acid sequence further comprises a hypermethylated promoter.  
     
     
         16 . The method of  claim 15 , further comprising a step of determining the amount of methylation of the SOCS-3 promoter following incubation with the test compound.  
     
     
         17 . The method of  claim 14 , wherein the increase in SOCS-3 activity is determined by measuring the level of SOCS-3 mRNA transcript.  
     
     
         18 . The method of  claim 14 , wherein the increase in SOCS-3 activity is determined by measuring the level of SOCS-3 polypeptide.  
     
     
         19 . A method of inhibiting proliferation of a cancer cell, the method comprising administering an agent that increases SOCS-3 activity to the cancer cell.  
     
     
         20 . The method of  claim 19 , wherein the cancer cell has a hypermethylated SOCS-3 promoter.  
     
     
         21 . The method of  claim 20 , wherein the cancer cell is selected from the group consisting of a lung cancer cell, a breast cancer cell, a mesothelioma cell, a colon cancer cell, and a sarcoma cell.  
     
     
         22 . The method of  claim 19 , wherein the agent is an expression vector encoding SOCS-3.  
     
     
         23 . The method of  claim 19 , wherein the agent is recombinant SOCS-3.  
     
     
         24 . The method of  claim 19 , wherein the agent is a demethylating agent.  
     
     
         25 . A kit comprising methylation-specific primers that are selective for methylated residues present within the region from -1005 to -983 or from -754 to -737 of SEQ ID NO:3.