Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

Abstract

Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported. We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families.

Cancer predisposing BARD1 mutations in breast–ovarian cancer families

“…Genes whose products are known to interact with BRCA1/2 and to be involved in DNA repair or cell cycle regulation are particularly attractive candidates for breast cancer susceptibility genes [22,60]. As a consequence, genes such as ATM, BRIP1, CHEK2, NBS1, PALB2, RAD50 and BARD1 have been analysed for the presence of germline mutations which may explain increased breast and/or ovarian cancer risk [8,12,16,23,35,38,43,46,48,50,[53][54][55].…”

BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer

“…BARD1 mutations are expected to account for additional cases of non-BRCA1/2 inherited BC, and have been reported in BRCAx BC families (Thai et al, 1998;Ghimenti et al, 2002;Ishitobi et al, 2003;Sauer et al, 2005, Karpinnen et al, 2006Stacey et al, 2006;Vahteristo et al, 2006;Huo et al, 2007;Gorringe et al, 2008;Jakubowska et al, 2008;Guenard et al, 2009;De Brakeleer et al, 2010). Most of them are missense …”

“…Small intragenic deletions (p.Leu359_Pro365del, 1144del21) have been described, but they occur with the same incidence in hereditary and sporadic BCs (Ghimenti et al, 2002;Ishtobi et al, 2003;De Brakeleer et al, 2010). Recently, a series of 196 blood DNA samples obtained from high-risk BC patients was analyzed for BARD1 deletions by real-time quantitative PCR (De Brakeleer et al, 2010).…”

Characterization ofLGALS3(galectin-3) as a player in DNA damage response

“…However, BARD1 tBRCT domain (located in its C-terminal) was also proven of functional relevance, depicted by cancer predisposing mutations affecting this domain. 19,20 The BARD1 tBRCT domain is also reported as an interaction domain, mediating protein-protein associations by specific phosphorylated motifs (e.g., pSer-X-X-Phe). 21 Curiously, the sequence Ser-Val-Phe-Pro-Phe-Glu-Ser (amino acids 188-194) found in the identified GAL3 fragment (Fig.…”