Abstract 3107: Association of alterations in homologous recombination repair genes with survival and chemotherapy sensitivity in patients with high-grade serous ovarian cancer

Abstract

Abstract Ovarian cancer is the most lethal gynecological malignancy worldwide. The poorest survival rate is found among the 60%-70% of patients diagnosed with advanced stage, high-grade serous ovarian cancer (HgsOvCa), which is also one of the major cancer types that have been systematically examined by The Cancer Genome Atlas (TCGA) project. It has been shown that mutations in BRCA2, a gene centrally involved in homologous recombination repair (HRR), is connected to platinum-sensitivity and better survival. The aim of this study was to obtain a comprehensive view of gene alterations in other central HRR genes, namely in ATM, ATR, MRE11A, RAD50, NBN, RAD52, RAD54L, RAD51, BARD1, XRCC2, XRCC3, BRCA1 and RPA1 in correlation to survival and platinum-sensitivity in HgsOvCa tumors. Copy number variation, mRNA expression and somatic mutation data along with detailed clinical data for 323 HgsOvCa samples were obtained from TCGA October 1, 2011. Each patient in the data set was treated with surgery followed by platinum-based therapy. In TCGA clinical data the patients were classified into four groups depending on the response to adjuvant chemotherapy. Of all patients 232 patients had experienced a complete or partial response (sensitive cases) and 36 had stable or progressive disease (resistant cases) after adjuvant chemotherapy. All the core interacting genes of HRR were screened in all samples and in different chemotherapy groups to see the effect of alterations of individual genes and in combination with other genes to the overall survival (OS), progression free survival (PFS) and chemotherapy response. The alterations that were screened included copy number amplifications and deletions, high and low mRNA expression (above or below z-score 2) and somatic mutations. The HRR genes were altered in 86% of all cases. The three genes having the most alterations were RPA1 (24%), NBN (24%) and ATR (23%). In two chemotherapy response groups, the main difference was seen in ATR. In sensitive group, ATR was altered in 24% of which in 88% the gene was either amplified or over expressed whereas in resistant group ATR was altered only in 8% of cases. However, ATR alone was not able to predict chemotherapy response or survival; analyses of the other genes are ongoing. Here we identified what types of alterations are present in central HRR genes in HgsOvCa. In addition we compared the landscapes of altered HRR genes in two different chemotherapy response groups. Future work, including methylation and functional studies, is needed to further identify and confirm the clinically relevant key alterations of HRR machinery that would eventually steer the finding of potential targets for improved therapies. 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 3107. doi:1538-7445.AM2012-3107