On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations.
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.
Program in Cancer Genetics, Department of Oncology, McGill University, Montreal, Quebec, Canada.
Nancy
N
Hamel
Bing-Jian
BJ
Feng
Lenka
L
Foretova
Dominique
D
Stoppa-Lyonnet
Steven A
SA
Narod
Evgeny
E
Imyanitov
Olga
O
Sinilnikova
Laima
L
Tihomirova
Jan
J
Lubinski
Jacek
J
Gronwald
Bohdan
B
Gorski
Thomas v O
Tv
Hansen
Finn C
FC
Nielsen
Mads
M
Thomassen
Drakoulis
D
Yannoukakos
Irene
I
Konstantopoulou
Vladimir
V
Zajac
Sona
S
Ciernikova
Fergus J
FJ
Couch
Celia M T
CM
Greenwood
David E
DE
Goldgar
William D
WD
Foulkes
D001938:Brazil / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007585:Jews; D018895:Microsatellite Repeats; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics; D044465:White People / Q000235:genetics*