Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms.

Abstract

BARD1 is the main binding partner of BRCA1 and is required for its stability and tumor-suppressor functions. In breast cancer and other epithelial cell carcinomas, alternatively spliced isoforms of BARD1 are highly upregulated and correlated with poor outcome. Recent data indicate that germline mutations of BARD1 may predispose to breast and/or ovarian cancer. To evaluate the role of BARD1 germline mutations in predisposition to ovarian cancer we scanned a cohort of 255patients for the presence of previously reported mutations located in exons5, 8 and10 using high-resolution melting analysis. Within this group we identified single-patients carrying mutation in exon8 (c.1690C>T, p.Gln564Ter), twodifferent variants in exon10 (c.1972C>T, p.Arg658Tyr; c.1977A>G, p.=) and a carrier of novel missense mutation located in exon5 (c.1361C>T, p.Pro454Leu). Three out of four identified mutations alter exonic splicing enhancing motives and result in expression of incorrect splicing skipping of exons5, 8, and2-9, respectively. Our data indicate that BARD1 variants may predispose to ovarian cancer in limited number of patients although based on actual data it is difficult to estimate its actual penetrance.