Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families

Abstract

The Quebec population contains about six-million French Canadians, descended from the French settlers who colonized "Nouvelle-France" between 1608 and 1765. Although the relative genetic contribution of each of these founders is highly variable, altogether they account for the major part of the contemporary French-Canadian gene pool. This study was designed to analyze the role of this founder effect in the introduction and diffusion of the BRCA1 recurrent R1443X mutant allele. A highly conserved haplotype, observed in 18 French-Canadian families and generated using 17 microsatellite markers surrounding the BRCA1 locus, supports the fact that the R1443X mutation is a founder mutation in the Quebec population. We also performed haplotyping analysis of R1443X carriers on 19 other families from seven different nationalities; although the same alleles are shared for three markers surrounding the BRCA1 gene, distinct haplotypes were obtained in four families, suggesting multiple origins for the R1443X mutation. Ascending genealogies of the 18 French Canadian families and of controls were reconstructed on an average depth of 10 generations. We identified the founder couple with the highest probability of having introduced the mutation in the population. Based on the descending genealogy of this couple, we detected the presence of geographical concentration in the diffusion pattern of the mutation. This study demonstrates how molecular genetics and demogenetic analyses can complement each other to provide findings that could have an impact on public health. Moreover, this approach is certainly not unique to breast cancer genetics and could be used to understand other complex traits.

Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia

“…Mutations c.4065_4068del4 and p.Arg1443X were found in Sweden [31], p.Arg1443X in the Sicilian population [26] as well as in the French population as a founder mutation [32]. Other Slovak low frequency BRCA1 pathogenic mutations were not occuring in any European HBOC report.…”

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

“…BRCA1-interacting gene variants in BOC families F Guénard et al have to keep in mind that the greater extent of LD generally found in the French Canadian population can be responsible for a lower number of haplotype blocks. 56 In addition such a difference between HapMap and this study may be due to the higher coverage of the gene regions in the HapMap data set which include both exonic and intronic SNPs, the latter not assessed in our study. The analysis of the coding region of the AURKA, BAP1, BARD1 and DHX9 genes did not identify any deleterious truncating mutation or aberrant splicing mRNAs.…”

Genetics, Tumor Features and Treatment Response of Breast Cancer in Latinas

“…Ethnic origin of some BRCA mutation described in Latin American countries has been confirmed as Jewish (c.68 69delAG) [70], Spanish (BRCA1 c.211A>G and BRCA2 c.2808 2811del4), Portuguese (BRCA2 c.156 157insAlu), Irish (BRCA2 c.5946delT), Baltic-zone origin (BRCA1 c.5266dupC) [21], French (BRCA1, c.4327C>T and BRCA1 4945 4947delAGAinsTTTT) [71], Sudafrican and African-American (c.5324T>G and c.824 825insAGCCATGTGG in BRCA1, and c.1310 1313delAAGA and c.3365 3366delCA in BRCA2) [72].…”