Predisposition to breast cancer by mutations at the ataxia-telangiectasia genetic locus

Abstract

The present invention relates generally to the field of human genetics. Specifically, the present invention relates to the discovery that some alleles of the A-T gene cause susceptibility to cancer, in particular breast cancer. More specifically, the present invention relates to germline mutations in the A-T gene and their use in the diagnosis of predisposition to breast cancer. The invention further relates to somatic mutations in the A-T gene in human breast cancer and their use in the diagnosis and prognosis of human breast cancer.

What is claimed is:  
     
         1 . A method for detecting an alteration in an A-T gene wherein said alteration is associated with breast cancer in a human, wherein if said alteration is in germline it is associated with predisposition to said breast cancer and if said alteration is in somatic tissue it indicates that said somatic tissue is cancerous, wherein said method comprises analyzing an A-T gene or an A-T gene expression product from a tissue of said human.  
     
     
         2 . The method of  claim 1  wherein said alteration is selected from the group consisting of 3245 ATC→TGAT, 8269 del 150, 2689 del 5, 1402 del AA, 1216 del GAAA and 9000 T→C.  
     
     
         3 . The method of  claim 1  wherein said expression product is RNA.  
     
     
         4 . The method of  claim 3  wherein said alteration of wild-type A-T RNA is detected by hybridization of said RNA to a A-T probe.  
     
     
         5 . The method of  claim 1  wherein said alteration of the A-T gene is detected by observing shifts in electrophoretic mobility of single-stranded DNA on non-denaturing polyacrylamide gels.  
     
     
         6 . The method of  claim 1  wherein said alteration of the A-T gene is detected by hybridization of an A-T gene probe to genomic DNA isolated from said tissue.  
     
     
         7 . The method of  claim 1  wherein said alteration of A-T gene is detected by amplifying all or part of said A-T gene in said tissue to produce an amplified DNA and sequencing said amplified DNA.  
     
     
         8 . The method of  claim 1  wherein said alteration of the A-T gene is detected by molecularly cloning all or part of said A-T gene from said tissue to produce a cloned DNA and sequencing said cloned DNA.  
     
     
         9 . The method of  claim 1  wherein said alteration of the A-T gene is detected by identifying a mismatch between molecules (1) A-T mRNA or cDNA made from mRNA isolated from said tissue and (2) a nucleic acid probe complementary to said human wild-type A-T DNA, when molecules (1) and (2) are hybridized to each other to form a duplex.  
     
     
         10 . The method of  claim 1  wherein said alteration of the A-T gene is detected by amplification of A-T DNA from said tissue to produce amplified A-T DNA and hybridization of said amplified A-T DNA to nucleic acid probes which comprise wild-type A-T sequences.  
     
     
         11 . The method of  claim 1  wherein said alteration of the A-T gene is detected by amplification of A-T DNA from said tissue to produce amplified CtIP DNA and hybridization of said amplified A-T DNA to nucleic acid probes which comprise non-wild-type A-T sequences.  
     
     
         12 . The method of  claim 1  wherein said alteration of the A-T gene is detected by in situ hybridization of said A-T with nucleic acid probes which comprise said A-T.  
     
     
         13 . The method of  claim 1  wherein said expression product is A-T protein.  
     
     
         14 . The method of  claim 13  wherein said alteration of A-T protein is detected by immunoblotting.  
     
     
         15 . The method of  claim 13  wherein said alteration of A-T protein is detected by immunocytochemistry.  
     
     
         16 . An isolated, altered A-T gene DNA, wherein said alteration is selected from the group consisting of 3245 ATC→TGAT, 8269 del 150, 2689 del 5, 1402 del AA, 1216 del GAAA and 9000 T→C.  
     
     
         17 . A nucleic acid probe complementary to human altered A-T gene sequences, wherein said nucleic acid probe hybridizes to an altered A-T gene sequence having 3245 ATC→TGAT, 8269 del 150, 2689 del 5, 1402 del AA, 1216 del GAAA and 9000 T→C under hybridization conditions at which said nucleic acid probe does not hybridize to wild-type A-T gene sequences.  
     
     
         18 . An isolated antibody immunoreactive with an altered A-T protein and not with a wild-type A-T protein wherein said altered A-T protein has an alteration resulting from an altered A-T gene having 3245 ATC→TGAT, 8269 del 150, 2689 del 5, 1402 del AA, 1216 del GAAA and 9000 T→C.