On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

• Published in: European journal of human genetics : EJHG Vol. 19; no. 3; pp. 300 - 306
• Main Authors: Hamel, Nancy, Feng, Bing-Jian, Foretova, Lenka, Stoppa-Lyonnet, Dominique, Narod, Steven A, Imyanitov, Evgeny, Sinilnikova, Olga, Tihomirova, Laima, Lubinski, Jan, Gronwald, Jacek, Gorski, Bohdan, Hansen, Thomas v O, Nielsen, Finn C, Thomassen, Mads, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Zajac, Vladimir, Ciernikova, Sona, Couch, Fergus J, Greenwood, Celia M T, Goldgar, David E, Foulkes, William D
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2011
• Subjects: AJ gene; Brazil; Brazil - epidemiology; BRCA1 protein; Breast cancer; Breast Neoplasms; Breast Neoplasms - epidemiology; Breast Neoplasms - genetics; Cancer; Ethnic Groups; Ethnic Groups - genetics; Europe; Europe - epidemiology; European Continental Ancestry Group; European Continental Ancestry Group - genetics; Female; Founder Effect; Gene Frequency; Gene pool; Genes; Genes, BRCA1; Genetic markers; Genetic Predisposition to Disease; Genetic screening; Genetic Testing; Genetics; Genotype; Haplotypes; Hospitals; Humans; Jews; Laboratories; Life Sciences; Maximum likelihood method; Medical research; Microsatellite Repeats; Microsatellites; Molecular evolution; Mutation; Oncology; Ovarian cancer; Ovarian Neoplasms; Ovarian Neoplasms - epidemiology; Ovarian Neoplasms - genetics; Population; Population studies; Recombination; Brazil; Europe; Greece; Canada; Latvia; United States > US; Quebec Canada; Denmark; Poland; Montreal Quebec Canada; Toronto Ontario Canada; France; Russia
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2010.203

The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allows for both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400-500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.