Abstract 3054: Expression of miR367* confers a “BRCAness” phenotype in epithelial ovarian cancer.

Abstract

Abstract Patients with hereditary epithelial ovarian cancer (EOC) associated with germline BRCA1/2 mutations exhibit improved outcome and high sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors (PARPis) due to an underlying defect in DNA repair via homologous recombination (HR). Importantly, a subset of patients with sporadic EOCs also exhibit improved outcome and responsiveness to these cytotoxic agents - a phenotype commonly referred to as "BRCAness" - possibly due to defective HR caused by mechanisms unrelated to germline mutation in BRCA-1 or 2. Here, we report that expression of miR-367* in EOC tumors without genetic or epigenetic alterations of HR pathway genes is associated with a “BRCAness” phenotype. We accessed data from 313 high grade serous EOCs included in The Cancer Genome Atlas (TCGA) EOC dataset. For all these tumors gene expression, DNA copy number, promoter methylation and whole-exome DNA sequencing information was available. Approximately 50% of these tumors (154 of 313) had known genetic or epigenetic alterations in HR pathway genes, including somatic or germline BRCA1/2 mutations, hypermethylation of BRCA1 or RAD51C, amplification or mutation of EMSY, focal deletion or mutation of PTEN, mutation of ATM or ATR, and mutation of Fanconi anemia genes. We focused on the remaining 159 tumors that did not harbor genetic or epigenetic alterations in HR pathway and used miRNA Agilent array expression data from these tumors to correlate expression of miR-367* with outcome and platinum sensitivity. Among these 159 tumors without known genetic or epigenetic alterations of HR pathway genes, those tumors whose expression level for miR-367* was in the top tertile, were associated with improved overall survival (OS) and progression free survival (PFS), (hazard ratio for death was 0.604, p=0.033 and for progression was 0.599, p=0.025). Similar associations with OS and PFS were identified when miR-367* expression was evaluated as a continuous variable (p=0.013 for OS and p=0.029 for PFS). Furthermore, among these 159 tumors without known genetic or epigenetic alterations of HR pathway genes, those tumors whose expression level for miR-367* was in the top tertile were more likely to be platinum sensitive (71% vs 50% respectively, two sided p=0.069). Finally, induced expression of miR-367* in ovarian cancer cell lines enhanced sensitivity to DNA double strand break-inducing agents, such as carboplatin and the PARPi olaparib in vitro. These data suggest that expression of miR-367* is associated with a “BRCAness” phenotype in EOC, i.e. improved outcome and sensitivity to platinum and PARPis. We are currently investigating whether miR-367* may interfere directly with DNA repair via HR in vitro. Citation Format: Alexander Morse, Chiara Battelli, Hai Hu, Elena Levantini, Gerburg Wulf, Youngeun Choi, Dipanjan Chowdhury, Panagiotis Konstantinopoulos. Expression of miR367* confers a “BRCAness” phenotype in epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3054. doi:10.1158/1538-7445.AM2013-3054