CHEK2 is a human homologue of yeast Cds1 and Rad53 which encodes the cell cycle checkpoint kinase. CHEK2 is activated by phosphorylation by ATM in response to double-strand DNA breaks.^1,2 Activated CHEK2 in turn phosphorylates and activates p53, which triggers cell cycle arrest at G1 or apoptosis.^3,4 CHEK2 also phosphorylates Cdc25C, preventing cellular entry into mitosis after DNA damage.² Thus, CHEK2 plays an important role in the network of cell cycle regulation and DNA damage repair, which are crucial processes in preventing cancer development.

CHEK2*1100delC leads to premature termination of translation and abolishes the kinase activity of the encoded protein. Although an initial report described germline CHEK2 mutations in Li-Fraumeni syndrome (LFS),⁵ subsequent studies have shown that CHEK2*1100delC is a low penetrance variant conferring an increased susceptibility to breast cancer with a relative risk of 2.0, not a high penetrance allele responsible for LFS.^6,7 In addition, CHEK2*1100delC also may be associated with other cancers. A recent study suggested that CHEK2*1100delC may contribute significantly to familial prostate cancer (p = 0.02).⁸ Another study suggests that CHEK2*1100delC is over-represented in breast cancer families with colorectal cancers (hereditary breast and colorectal cancer, HBCC) as compared with families with breast cancer only (non-HBCC).⁹ We previously reported that women with multiple primary cancers (breast and any other cancer) are more likely to have BRCA1 and BRCA2 mutations than matched individuals with breast cancer only.¹⁰ Here we asked whether a similar sample of women with multiple primary cancers, one of which was breast cancer, had an excess of CHEK2*1100delC compared to controls. Thus, we examined the frequency of CHEK2*1100delC in constitutional DNA from 161 women with multiple primary cancers (one primary was always breast cancer) as compared to a matched …