Abstract 3116: Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in ovarian cancer

Abstract

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: BRCA1 and BRCA2 are key members of the homologous recombination (HR) pathway. Mutations in these genes and other HR pathway defects have potential therapeutic relevance when used to support agents that introduce or exploit double-strand DNA breaks. This study examines the association between HR deficiency and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumors from two independent datasets were characterized for germline and somatic defects in BRCA1 and BRCA2. Whole genome LOH profiles were generated using Affymetrix SNP arrays. Publically available data was downloaded from the TCGA website for a third independent ovarian cancer dataset. RAD51C promoter methylation was assayed in two of the datasets. Comprehensive profiling of BRCA1 and BRCA2 defects, and genome wide LOH was also performed on approximately 70 breast, ovarian, colon and pancreatic cell lines. Results: Examination of the pattern of LOH within ovarian tumors with BRCA1, BRCA2, or RAD51C defects compared to tumors without defects in these genes has resulted in the development of a homologous recombination deficiency (HRD) score that has highly significant association with HRD (p=9*10-11). An intermediate class of LOH sizes (>15 Mb but less than a whole chromosome) is highly positive correlated with defective HR, suggesting this class of LOH exists due to double strand DNA break formation and requires repair by HR. The HRD score was validated in two independent ovarian cancer datasets (p=2*10-7 and 9*10-29), and successfully identified breast and pancreatic cell lines with BRCA defects, suggesting it will be effective across multiple tumor types. Conclusions: BRCA1 or BRCA2 mutation carriers have improved outcomes following treatment with DNA damaging agents such as platinum salts, and preclinical studies have demonstrated PARP inhibitor efficacy in BRCA1 or BRCA2 deficient cells. HR deficiency in ovarian cancer is not solely due to germline BRCA1 and BRCA2 mutations, and HR deficiency is not unique to ovarian tumors. Each type of cancer is likely to have a unique spectrum of genetic variants resulting in HRD. The HRD score appears capable of detecting HRD regardless of etiology or mechanism. This score could have clinical utility in breast and ovarian cancer, and could be used to target the use of PARP inhibitors and platinum salts in other cancers. 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 3116. doi:1538-7445.AM2012-3116