Compositions and methods relating to DNA mismatch repair genes

Abstract

Genomic sequences of human mismatch repair genes and gene products are described, as are methods of detecting mutations and/or polymorphisms in those genes. Also described are methods of diagnosing cancer susceptibility in a subject, and methods of identifying and classifying mismatch-repair-defective tumors. In particular, sequences and methods relating to human mutL homologs, hMLH1 and hPMS1 genes and gene products are provided.

We claim:  
     
         1 . A method of determining whether a person is susceptible to cancer comprising: 
 collecting a sample from the person,    contacting the sample with antibodies that bind specifically to a mutL homolog protein, and    detecting binding or lack of binding antibodies to mutL homolog protein.    
     
     
         2 . The method of  claim 1  comprising specific binding of antibodies to hMLH1 protein as shown in SEQ ID NO: 5.  
     
     
         3 . The method of  claim 1 , wherein the antibodies are polyclonal.  
     
     
         4 . The method of  claim 1 , wherein the antibodies are monoclonal.  
     
     
         5 . The method of  claim 1 , wherein the antibodies are conjugated to a fluorescent compound.  
     
     
         6 . A method of determining whether tumor tissue has a deficient amount of a mutL homolog protein comprising 
 obtaining a cross-section of a tumor specimen,    contacting the cross-section with a purified antibody that binds specifically to a mutL homolog protein, and    determining the presence or absence of antibody bound to a mutL homolog protein in the cross-section.    
     
     
         7 . The method of  claim 6 , wherein the antibody is a monoclonal antibody.  
     
     
         8 . The method of  claim 6 , wherein the antibody is a polyclonal antibody.  
     
     
         9 . The method of  claim 6 , wherein the antibody is conjugated to a fluorescent compound.  
     
     
         10 . The method of  claim 6  further comprising 
 prescribing a therapy regimen based at least partially on results of the determining step.  
 
     
     
         11 . The method of  claim 6  further comprising 
 eluting unbound antibody from the cross-section.  
 
     
     
         12 . The method of  claim 6 , wherein the antibody binds specifically to hMLH1 protein.  
     
     
         13 . A method of manufacturing antibodies that bind specifically to a mutL homolog protein comprising 
 synthesizing or isolating at least a portion of a mutL homolog protein,    overexpressing the protein in bacteria,    purifying the protein,    injecting the protein into a mouse,    generating a hybridoma by fusing a lymphocyte from the mouse with a myeloma cell, and    isolating monoclonal antibodies produced by the hybridoma, wherein the antibodies bind specifically to a mutL homolog protein.    
     
     
         14 . The method of  claim 13 , wherein the monoclonal antibodies bind specifically to hMLH1 protein as shown in SEQ ID NO: 5.