Identification Of Recurrent Mutations In BRCA1/2 Across Multiple Cancers In Chinese Population

Objective: Thoroughly investigate the potential relationships of BRCA1/2 mutations between breast cancer and other cancers,identify the functions of most recurrent mutation in breast cancer cells.Materials and methods: We performed a two-stage study to screen BRCA1/2mutations with 7582 cancer cases and 4874 cancer-free controls,consisting of a discovery stage with 70 familial?breast cancer cases and a subsequent validation stage with 7512 cases(3217 breast cancer,1133 cervical cancer,2044 hepatocellular carcinoma and 1116 colorectal cancer).We further evaluated the effects of the most promisingly novel mutation on breast cancer cell lines proliferation and migration in vitro.Results: We obtained 48 variants in BRCA1/2 after scanning 70 familial breast cancer cases and finally selected 22 likely deleterious mutations containing frameshift or missense mutations for subsequent validation.Seven novel mutations were identified.Among five recurrent mutations(BRCA1 c.3257 del T,c.4801A>T,c.441 del T and BRCA2 c.4307T>C,c.7409 dup T)observed in multi-cancers,two mutations(BRCA1 c.3257 del T,and c.441 del T)were novel and specific in breast cancer cases.Moreover,BRCA1 c.3257 del T was the most frequently only in Chinese sporadic breast cancer and showed noteworthy result especially in functional verification of triple-negative breast cancer cell lines,it reduced m RNA and protein expressions of BRCA1 and increased the cell proliferation.Conclusions: We performed a two-stage study to screen BRCA1/2 mutations in Chinese population and observed recurrent mutations(BRCA1 c.3257 del T,c.4801A>T,c.441 del T and BRCA2 c.4307T>C,c.7409 dup T)in multi-cancers.Moreover,we emphasize the potential biological function of BRCA1 c.3257 del T in triple-negative breast cancer,it could be considered as candidate genetic loci for breast cancer screening in Chinese population.