Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

Abstract

Breast cancer is a heterogeneous disease displaying some degree of familial clustering. Highly penetrant breast cancer susceptibility genes represent approximately 20-25% of the familial aggregation of breast cancer. A significant proportion of this familial aggregation of breast cancer is thus yet to be explained by other breast cancer susceptibility genes. Given the high susceptibility conferred by the two major breast cancer predisposition genes, BRCA1 and BRCA2 and the implication of these genes in many key cellular processes, assessment of genes encoding BRCA1-interacting proteins as plausible breast cancer candidate genes is thus attractive. In this study, four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. Although no deleterious truncating germline mutations or aberrant spliced mRNA species were identified, a total of 10, 4, 11 and 6 variants were found in the AURKA, BAP1, BARD1 and DHX9 genes, respectively. The allele frequency of each variant was further ascertained in a cohort of 98 healthy French Canadian unrelated women and a difference in allele frequency was observed for one BARD1 variant based on single-marker analysis. Haplotype estimation, haplotype blocks and tagging SNPs identification were then performed for each gene, providing a valuable tool for further searches of common disease-associated variants in these genes and therefore further analyses on these genes in larger cohorts is warranted in the search of low-to-moderate penetrance breast cancer susceptibility alleles.

Lack of association between BARD1 Cys557Ser variant and breast cancer risk: a meta-analysis of 11,870 cases and 7,687 controls

“…Pervious studies have described that no signiWcant associations were found between Cys577Ser mutation and breast cancer risk in Poland, Canada, Sweden, and Australia (Gorringe et al 2008;Jakubowska et al 2008;Guénard et al 2009;Johnatty et al 2009;Ratajska et al 2011). The discrepancy between the present studies could be due to the population controls used, which may have resulted in a positive association by chance.…”

“…A total of nineteen studies with full-text articles examined the association of Cys557Ser mutation with breast cancer were found (Thai et al 1998;Ghimenti et al 2002;Karppinen et al 2004;Tarasov et al 2006;Onay et al 2006;Vahteristo et al 2006;Stacey et al 2006;Karppinen et al 2006;Gorringe et al 2008;Jakubowska et al 2008;Guénard et al 2009;Johnatty et al 2009;Spurdle et al 2011;Ratajska et al 2011). Among them, the study of Karppinen et al was excluded because they investigated almost the same population reported before.…”

“…And ectopically expressed Cys557Ser protein shows defects in growth-suppressive and pro-apoptotic functions, suggesting that the variant may have some impact on cancer predisposition (Sauer and Andrulis 2005). To date, many epidemiological studies have evaluated the association between Cys557Ser variant and breast cancer risk, but the results remain conXicting rather than conclusive (Thai et al 1998;Ghimenti et al 2002;Karppinen et al 2004;Tarasov et al 2006;Onay et al 2006;Vahteristo et al 2006;Stacey et al 2006;Karppinen et al 2006;Gorringe et al 2008;Jakubowska et al 2008;Guénard et al 2009;Johnatty et al 2009;Spurdle et al 2011;Ratajska et al 2011). In an attempt to resolve these contradictory results, we performed this meta-analysis to assess whether combined evidence shows the association between BARD1 Cys557Ser and breast cancer risk.…”

Features of Double-stranded RNA-binding Domains of RNA Helicase A Are Necessary for Selective Recognition and Translation of Complex mRNAs

“…The possibility remains that the N-terminal dsRBD(s) interact with distal RHA domains; future experiments to test this model are warranted. The results will contribute to understanding the essential role of RHA in normal cells and the apparent contribution of RHA dysfunction to neoplastic growth (35)(36)(37). The outcomes will fuel fundamental understanding of RNA helicases across cell biology and at the virushost interface.…”

Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair

“…In support of BAP1 functioning as a tumor suppressor, several recent publications have identified BAP1 mutations in various forms of cancer (31)(32)(33)(34)(35)(36). Germline mutations in BAP1 have been shown to predispose patients to uveal melanoma, lung carcinoma, meningioma, and melanocytic tumors (31)(32)(33)(34)(35)(36). BAP1 is also commonly inactivated by somatic mutations and/or its location on chromosome 3p21.1 is lost in malignant pleural mesotheliomas (MPM; ref.…”