Abstract 2981: Association of a BRCAness profile with outcome and molecular aberrations involving homologous recombination in the TCGA ovarian cancer dataset
Authors: Tchekmedyian Nishan , Morse Alexander , Srisowmya Sanisetty , Cannistra Stephen A. , Konstantinopoulos Panagiotis A. 
Published: August 2012

Abstract
A subset of sporadic epithelial ovarian cancer (EOCs) may harbor a “BRCAness” phenotype characterized by improved outcome and enhanced responsiveness to platinum analogues and PARP inhibitors, similar to their BRCA1/2 mutated counterparts. This BRCAness phenotype may be due, in part, to defective homologous recombination (HR) related to various mechanisms, including BRCA1 promoter hypermethylation, somatic mutation of BRCA1/2 genes, or loss of function mutations in other HR pathway genes. We recently defined a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in EOC. Here, we used The Cancer Genome Atlas (TCGA) EOC dataset to evaluate the association of the BRCAness profile with outcome, chemotherapy response and specific molecular aberrations that may underlie defective HR. We accessed data from 265 advanced stage high grade serous EOCs for which there was available gene expression, DNA copy number, promoter methylation and whole-exome DNA sequencing information. Patients were characterized as having a BRCAness phenotype (BL profile) or not (NBL profile) based on our BRCAness signature. BL patients were associated with improved median overall survival (OS) compared to NBL patients (59 vs 41 months respectively, log-rank p=0.008). Multivariable analysis demonstrated that the BRCAness profile maintained an independent association with OS (HR=1.72, p=0.024). BL patients had a longer median platinum free interval compared to NBL patients (17 vs 11 months, p=0.024) and improved median disease free survival (18 vs 14 months, p=0.055). BRCAness profile was associated with molecular events affecting BRCA1/2 function such as BRCA1/2 mutations, BRCA1 promoter hypermethylation and EMSY amplification (47% in BL patients vs 27% in NBL patients, two-sided Fisher's exact p=0.007). Furthermore, BL patients had higher frequency of homozygous PTEN deletion compared to NBL patients but this did not reach statistical significance (12% vs 6% respectively, two-sided Fisher's exact p=0.14). Conversely, BRCAness profile was not associated with molecular events affecting the function of other Fanconi Anemia (FA) genes (FANCA/B/C/D2/E/F/G/I/J/L/M, PALB2) or DNA damage response genes involved in HR (ATM, ATR, CHEK1, CHEK2) although the overall incidence of these molecular events was very low (5% and 3% respectively). In conclusion, the BRCAness profile may identify patients with improved outcome, responsiveness to chemotherapy, and those who harbor certain molecular aberrations involving HR. Efforts to improve the predictive ability of the BRCAness profile using gene expression data from the TCGA dataset are underway.
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 2981. doi:1538-7445.AM2012-2981