Founder BRCA1/2 mutations in the Europe: Ashkenazi Jews
Posted Jul 20 2010 10:45am
The BRCA1/2 founder effect in Ashkenazi Jews population is very well described. About 10 millions Ashkenazi people living worldwide are descendants of ancestors from Eastern and Central Europe, such as Poland, Lithuania, Belarus, Germany, Hungary, Ukraine and Russia. The most well characterized three founder mutations are two in BRCA1 gene c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT) [ 31 – 33 ]. Screening for these three founder mutations alone is now part of routine clinical practice for Ashkenazi Jewish individuals.
These 3 mutations (BRCA1 c.68_69delAG, c.5266dupC and BRCA2 c.5946delT) account for 98–99% of identified mutations and are carried by about 2.6% (1/40) of the Ashkenazi Jewish population (1%, 0.13% and 1.52% respectively) [ 34 – 36 ]. There are differences between particular mutations and breast/ovarian cancer risk [ 37 ]. The average risk of breast cancer by the age of 70 years is similar for carriers of the BRCA1 c.68_69delAG and c.5266dupC mutations (64% and 67% respectively), however is much lower for the c.5946delT mutation (43%). The corresponding values for ovarian cancer lifetime risk is respectively of 14%, 33% and 20% in carriers, respectively [ 6 , 37 , 38 ].
It is worth noting that BRCA1 c.68_69delAG and c.5266dupC are not found exclusively in Ashkenazi patients. The c.68_69delAG mutation has been found in patients of Spanish ancestry (i.e. Hispanic) as well as other non-Ashkenazi ethnic groups, sometimes with frequencies similar to those in Ashkenazi populations [ 3 ], suggesting a common ancient ancestor or two independent mutational events [ 39 ].
The c.5266dupC mutation in BRCA1 exon 20 is the second most frequently reported mutation in the BIC database, being very prevalent in Central and Eastern Europe. This single mutation is found in a various frequency in high risk breast and/or ovarian cancer families from Poland (34%) [ 40 ], Russia (14%) [ 41 ], Hungary (14%) [ 42 ], Slovenia (13%) [ 43 ], Ashkenazi Jews (10%) [ 44 ], Greece (8%) [ 45 ], Germany (4%) [ 46 ], Italy (3%) [ 47 ]. It is virtually absent in Spain and Portugal and is found at low frequency in the Netherlands, Belgium and Scandinavian countries [ 6 ]. In Russia, Belarus, Poland, Latvia, Czech Republic, Greece and Lithuania this mutation accounts for respectively 94% [ 48 ], 73% [ 49 ], 60% [ 40 ], 55% [ 50 ], 37–52% [ 51 , 52 ], 46% [ 45 ], 34% [ 53 , 54 ] of all BRCA1 mutations.
Haplotype analysis points to the Baltic origin of this mutation approximately 38 generations ago during the medieval period [ 55 ], with a gradual decrease thereafter from East to the West and nearly worldwide spread. A common ancestor for c.5266dupC mutation families reported from Europe, Brazil and North America is evident [ 46 , 56 , 57 ].