If breast cancer genetics were a game of chess, we wouldn't be close to winning it yet. We've taken two pieces off the board — BRCA1 and BRCA2 — but mutations in these genes account for only a small fraction of breast cancers. Hanne Meijers-Heijboers et al. have now claimed another pawn: they report in Nature Genetics that a truncating mutation in a cell-cycle checkpoint kinase, called CHEK2, might be responsible for 1% of all female breast cancer cases and 9% of all male breast cancer cases.

The authors screened families that did not have mutations in either BRCA1 or BRCA2, but did have a history of breast cancer, for the CHEK2*1100delC mutation. This mutant gene yields a protein that is devoid of kinase activity in vitro. Of the 1,071 individuals screened, 55 (5.1%) carried the CHEK2*1100delC mutation, compared with only 18 of 1,620 (1.1%) of control individuals. When these numbers were broken down further, a striking 13.5% of individuals from families that included cases of male breast cancer carried the variant. The authors conclude that in breast cancer families without BRCA1 or BRCA2 mutations, CHEK2*1100delC confers a twofold increased risk of breast cancer in women and a tenfold increased risk in men.

The mutation does not increase the risk of breast cancer in people carrying mutations in BRCA1 or BRCA2. This is consistent with previous studies showing that BRCA1 and CHEK2 participate in the same biochemical pathway, and also indicates that CHEK2 might share a common biochemical pathway with BRCA2.

The CHEK2 protein is activated by the DNA-damage-activated kinase ATM. CHEK2 blocks entry into mitosis at the G2 phase by activating p53 and inhibiting the pro-mitotic tyrosine phosphatase CDC25C. Consequently, cells with null mutations in CHEK2 cannot stop and repair damaged DNA; this leads to genomic instability and, potentially, cancer.

So far, the authors have screened only for the CHEK2*1100delC mutation; other mutations in the same gene might also be expected to contribute to breast cancer risk, with varying penetrance depending on the severity of the mutation. So, the finding of this low-penetrance susceptibility gene for breast cancer might allow us to remove several pieces from the chess board.