Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom's syndrome, is associated with breast cancer in Slavic populations.

Bloom's syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case-control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case-control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel-Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10(-4)). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10(-5)). Altogether, these data indicate that BLM is not only a gene for Bloom's syndrome but also might represent a breast cancer susceptibility gene.