Genetic susceptibility towards breast cancer – First results from the HMBCS case-control association study

We present first results of the Hannover-Minsk Breast Cancer Study (HMBCS) that aims to elucidate the genetic basis of breast cancer susceptiblity in the ethnically homogeneous population of Belarus. We report twelve susceptibility alleles at eight genomic loci in a large case-control series of 1759 breast cancer cases and 1019 population controls. Three mutations in the BRCA1 gene (5382insC, 4153delA, T300G) and one mutation in the BRCA2 gene (6174delT) accounted for a total of 79 Byelorussian breast cancer patients (4.5%). In contrast with published data, the BRCA1*4153delA mutation was clearly associated with an increased breast cancer risk in our study population (OR 4.7, p=0.02). Furthermore, five founder mutations in the CHEK2 (n=3), NBN and ATM genes were each associated with breast cancer and together accounted for 147 Byelorussian breast cancer cases (8.4%). The results on CHEK2 mutations indicate higher risks for two truncating mutations compared with one missense mutation. In addition, common low-penetrance alleles at three genomic loci, two near the FGFR2 and TOX3 genes and one on chr2q35, were significantly associated with breast cancer. Taken together, the data indicate that there are at least three classes of breast cancer susceptibility alleles: (i) rare mutations associated with high risks and familial aggregation, (ii) mutations with low to moderate frequencies associated with two- to fourfold increases in risk, and (iii) common single nucleotide variants associated with some 20–50% increases in risk. This approach may help to identify and stratify individuals with different genetic risks for clinical research and perhaps for future preventive and therapeutic measures.

ATM - BRCA1 - CHEK2 - NBS1 - low-penetrance susceptibility