Abstract 2602: CHEK2 contribution to hereditary breast cancer in non-BRCA famillies

Abstract

Abstract Mutations in the BRCA1 and BRCA2 genes are responsible for only a part of hereditary breast cancer (HBC). The origins of “non BRCA” HBC families may be attributed in part to mutations in genes giving moderate risk, such as CHEK2. We investigated the contribution of CHEK2mutations to non-BRCA HBC by direct sequencing of its entire coding sequence. Fifteen mutations were discovered among 507 non-BRCAHBC cases and four among 513 controls. The frequency of CHEK2variants was significantly higher among cases (p= 0.0076), and gave an OR for breast cancer of 4.72 for deleterious mutation carriers. We then used both in silico tools and in vitro kinase activity to evaluate recombinant mutant proteins. Tumor characteristics and tumor grade of paraffin-embedded tissue blocks from 8 CHEK2 mutated patients were evaluated by histology. To further characterize those tumors, breast cancer immunohistochemical markers such as hormone receptors, HER2 and P53 were assessed. Because the mechanisms of tumorigenesis in association with CHEK2 variants are still unclear, we performed genetic and epigenetic analysis of those tumors. Three relevant SNPs spanning the CHEK2 gene locus were used to determine loss of heterozygosity (LOH). Also, the proximal CpG islands of the CHEK2 gene were investigated for hypermethylation. Our results suggest a contribution of CHEK2 mutations to non-BRCA HBC, though the usefulness of moderate penetrance genes for genetic counseling remains controversial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2602. doi:1538-7445.AM2012-2602