Abstract 90: An evaluation of the genes involved in the Base Excision Repair (BER) pathway as potential phenotypic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

Abstract

Abstract Germ-line mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of developing breast and other cancers. However, remarkable differences exist regarding disease manifestation in mutation carriers, suggesting the existence of other genetic modifier factors. Given that both BRCA1 and BRCA2 are involved in the repair of double-strand breaks (DSBs) mainly by Homologous Recombination, SNPs in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers. The Base Excision Repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of this pathway, PARP1, and both BRCA1 and BRCA2. To test our hypothesis we have performed a comprehensive analysis of the 18 genes involved in BER, in a series of 2000 BRCA1 and BRCA2 mutation carriers from the Spanish Consortium for the Study of Hereditary Breast Cancer, the Istituto Nazionale Tumori and the National Centre for Scientific Research “Demokritos”. For this purpose we have used a tagging SNP approach in which we have evaluated the common genetic variation in the 18 genes using the VeraCode GoldenGate 144 SNP Genotyping Kit. Preliminary results have showed statistically significant associations with cancer risk in BRCA1 and/or BRCA2 mutation carriers for 46 SNPs (p<0.05), seven of them showing associations with p<10−3. Genetic and functional analyses are currently on-going to validate the most statistically significant effects. 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 90. doi:1538-7445.AM2012-90