Absence of the CHEK2*1100delC mutation in non-BRCA1/2 families with multiple cancer types in a high-risk clinic population of Caucasian ancestry

11040 Background: Checkpoint kinase 2(CHEK2) is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. The contribution of CHEK2 mutations to familial cancer has been widely studied in breast cancer. Most notably, the CHEK2*1100delC mutation has been characterized to confer a 2-fold increased risk for breast cancer in carriers. This finding comes from studies performed on Northern and Eastern European populations. Few studies, however, have been conducted in North American. In contrast to the work done in Europe, these studies suggest a lower frequency of CHEK2*1100delC mutations in breast cancer families. The aim of this study was to determine the frequency of CHEK2*1100delC in members of breast cancer families who tested negative for a deleterious mutation in BRCA1/2. Methods: DNA sequencing was used to genotype 115 individuals for CHEK2*1100delC. Families were characterized by the presence of several cases of breast and/or ovarian cancer and multiple members with other cancers in a single lineage. Given the broad variety of cancers associated with CHEK2 mutations and its function in DNA repair, we hypothesized that these families would be enriched for harboring the CHEK2*1100delC in the germline. Results: No CHEK2*1100delC mutations were detected in 115 individuals, including 39 women diagnosed with breast cancer at an early age, 7 women with bilateral cancer, 2 men with breast cancer and 6 women with ovarian cancer, all of whom were negative for mutations in BRCA1/2.The CHEK2 Breast Cancer Consortium previously reported a frequency of 2.3% for the CHEK2*1100delC mutation among breast cancer cases from families with at least 2 cases of breast cancer (or breast and ovarian cancer) in a first- or second-degree relationship. Based on that, we had approximately 92% power to detect at least one mutation among our study cohort. Conclusions: Our data are consistent with previous reports that suggest a lower frequency of CHEK2*1100delC mutations in North American hereditary breast cancer families without BRCA1/2 mutations and enriched for multiple cancer types. The low frequency of the CHEK2*1100delC in the North American population limits its clinical relevance as a cancer predisposing gene. No significant financial relationships to disclose.