Susceptibility to Breast Cancer in CHK2 Mutation Carriers

Familial breast cancer accounts for 15 to 35 of all breast cancers. Mutations in a number of genes are now known to cause susceptibility to breast cancer the most notorious are the BRCA1 and BRCA2 genes. However, it has become evident that not all and not even the majority of familial breast cancer families can be attributed to mutations in BRCA1 and BRCA2. In a recent study by the Breast Cancer Linkage Consortium, only one third of families with four or five cases of female breast cancer and no cases of ovarian cancer carry mutations in either BRCA1 or BRCA2. Because smaller familial clusters are much more common than families with large numbers of cases, the indication from these and other studies is that a substantial proportion of familial clustering is not accounted for by mutations in BRCA1 and BRCA2 therefore, there is a great need to discover other genes that contribute to this disease. Recently, it was reported that germline CHK2 mutations were found in two families with Li-Fraumeni syndrome and a third case with multiple primary cancers. The two families with Li-Fraumeni syndrome had diverse cancers, including early-onset breast cancers at ages 37, 41, and 45 years. The third proband developed breast cancer at age 47, malignant melanoma at 53 and primary lung cancer at 58, but had no family history of malignancies.