Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 27, No 15S (May 20 Supplement), 2009: 5528
© 2009 American Society of Clinical Oncology

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Abstract

Somatic BRCA status in ovarian tumors

University of Texas M. D. Anderson Cancer Center, Houston, TX; Myriad Genetics Inc, Salt Lake City, UT

5528

Background: The combined prevalence of BRCA1/2 mutations in germline DNA derived from a population of invasive ovarian cancer patients is up to 15.3%. PARP inhibitor trials are ongoing in patients who carry germline BRCA1/2 mutations. It is important to know whether somatic (non-germline) BRCA changes are present in ovarian tumors, given the predicted sensitivity of BRCA mutation-carrying tumors to PARP inhibitors and other DNA damaging agents. However, a large cohort of ovarian tumor tissues has not been studied to determine the frequency of BRCA deficiency due to additional somatic changes. Methods: BRCA1/2 exons/flanking regions were sequenced in 235 high-grade ovarian cancers and 38 ovarian cancer cell lines. In 112 tumors, we also performed gene expression analysis and copy number arrays with ultradense probe tiling throughout both BRCA genes. Results: For BRCA1, 31 tumors (13.2%) harbored mutations: 23 known deleterious mutations, 1 suspected deleterious mutation, 3 novel indels, 1 novel mis-sense and 3 novel nonsense mutations. For BRCA2, 12/178 sequenced tumors (6.7%) harbored mutations: 8 known deleterious mutations, 1 suspected deleterious mutation and 3 novel indels. Only 3 BRCA1 mutations were detected in 2 cell lines, two known deleterious and 1 a novel 29 base pair deletion. One cell line thus appears to have both a germline and a somatic mutation. BRCA mutation status was associated with a trend to improved progression-free survival (PFS) in univariate analysis (p = 0.17). However, BRCA deficiency (defined by BRCA1/2 gene expression loss (4 tumors) and homozygous deletion (1 tumor) in addition to mutations) was associated with improved PFS in univariate (p = 0.04) and multivariate (p = 0.03) analyses. Conclusions: The frequency of BRCA1/2 mutations in ovarian tumors detected by sequencing regardless of family history is 20%, higher than the expected prevalence of germline mutations. In both BRCA1/2 genes, almost 25% of mutations in tumor tissue were novel and not previously seen in germline DNA. We are now sequencing corresponding germline DNA to determine the exact number of these novel mutations that are somatic. Direct analysis of ovarian tumor tissue is likely to expand the number of women with BRCA-deficient tumors beyond that detectable by germline sequencing.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Genetics Inc Myriad Genetics Inc Myriad Genetics Inc

Abstract presentation from the 2009 ASCO Annual Meeting