Large deletions in human brca1 gene and use thereof

Abstract

Large deletions have been identified in the BRCA1 gene in patients. The large deletions predispose the patients to breast cancer and ovarian cancer. Thus, methods for detecting the genetic variants are provided which can be used in detecting a predisposition to cancer.

1 . A method for predicting a predisposition to cancer in a patient, comprising:
 detecting a deletion in the BRCA1 gene, said deletion resulting from the unequal crossover between a pair of repetitive sequences in the BRCA1 gene, where said pair of repetitive sequences is selected from the group consisting of:   (1) a first Alu sequence comprising basepairs 56,705-57,010, and a second Alu sequence comprising basepairs 63,044-63,346,   (2) a third Alu sequence comprising basepairs 54,676-54,965, and a fourth Alu sequence comprising basepairs 62,026-62,323,   (3) a fifth Alu sequence comprising basepairs 55,865-56,164, and said fourth Alu sequence comprising basepairs 62,026-62,323,   (4) said fifth Alu sequence comprising basepairs 55,865-56,164, and a sixth Alu sequence comprising basepairs 61,616-61,918,   (5) a seventh Alu sequence comprising basepairs 53,006-53,171, and an eighth Alu sequence comprising basepairs 58,500-58,798, and   (6) a ninth Alu sequence comprising basepairs 50,347-50,642, and a tenth Alu sequence comprising basepairs 76,803-77,098;   wherein the presence of the deletion would indicate a predisposition to cancer.   
     
     
         2 . The method of  claim 1  wherein the detection step comprises analysis of BRCA1 genomic DNA. 
     
     
         3 . The method of  claim 2  wherein the analysis of BRCA1 genomic DNA comprises amplifying a region of genomic DNA in which the deletion occurs. 
     
     
         4 . The method of  claim 2  wherein the analysis of BRCA1 genomic DNA comprises hybridizing a nucleic acid probe to a region of genomic DNA in which the deletion occurs. 
     
     
         5 . The method of  claim 1  wherein the detection step comprises analysis of BRCA1 cDNA. 
     
     
         6 . The method of  claim 5  wherein the analysis of BRCA1 cDNA comprises amplifying a region of cDNA in which the deletion occurs. 
     
     
         7 . The method of  claim 5  wherein the analysis of BRCA1 cDNA comprises hybridizing a nucleic acid probe to a region of cDNA in which the deletion occurs. 
     
     
         8 . The method of  claim 1  wherein the detection step comprises analysis of a BRCA1 polypeptide. 
     
     
         9 . The method of  claim 8  wherein the analysis of a BRCA1 polypeptide comprises determining whether the polypeptide is truncated. 
     
     
         10 . The method of  claim 8  wherein the analysis of a BRCA1 polypeptide comprises contacting the polypeptide with an antibody. 
     
     
         11 . The method of  claim 1  wherein said pair of repetitive sequences in the BRCA1 gene is selected from the group consisting of:
 (1) a first upstream sequence of basepairs 56,960-56,998, and a first downstream sequence of basepairs 63,296-63,334,   (2) a second upstream sequence of basepairs 54,960-54,965, and a second downstream sequence of basepairs 62,143-62,147,   (3) a third upstream sequence of basepairs 55,893-55,932, and a third downstream sequence of basepairs 62,049-62,088,   (4) a fourth upstream sequence of basepairs 56,090-56,095, and a fourth downstream sequence of basepairs 61,838-61,843,   (5) a fifth upstream sequence of basepairs 53,030-53,075, and a fifth downstream sequence of basepairs 58,659-58,704, and   (6) a sixth upstream sequence of basepairs 50,524-50,577, and a sixth downstream sequence of basepairs 76,977-77,031.   
     
     
         12 . The method of  claim 11  wherein the detection step comprises analysis of BRCA1 genomic DNA. 
     
     
         13 . The method of  claim 12  wherein the analysis of BRCA1 genomic DNA comprises amplifying a region of genomic DNA in which the deletion occurs. 
     
     
         14 . The method of  claim 11  wherein the detection step comprises analysis of BRCA1 cDNA. 
     
     
         15 . The method of  claim 11  wherein the detection step comprises analysis of BRCA1 polypeptides. 
     
     
         16 . The method of  claim 1 , wherein the deletion results in a BRCA1 genomic DNA comprising a nucleotide sequence selected from the group consisting of:
 (a) SEQ ID NO: 1,   (b) SEQ ID NO:2,   (c) SEQ ID NO:3,   (d) SEQ ID NO:4,   (e) SEQ ID NO:5, and   (f) SEQ ID NO:6.   
     
     
         17 . The method of  claim 16  wherein the detection step comprises amplifying a region of genomic DNA in which the deletion occurs. 
     
     
         18 . The method of  claim 16  wherein the detection step comprises hybridizing a nucleic acid probe to a region of genomic DNA in which the deletion occurs. 
     
     
         19 . An isolated mutant BRCA1 polypeptide comprising a sequence selected from the group consisting of:
 (a) SEQ ID NO:10,   (b) SEQ ID NO:11,   (c) SEQ ID NO 12,   (d) SEQ ID NO 13, and   (e) SEQ ID NO: 14.   
     
     
         20 . An isolated antibody specifically immunoreactive with the mutant BRCA1 polypeptide of  claim 19 .