Abstract 1543: Systematic functional assessment of driver mutations for individual ovarian cancers

Abstract

Abstract Although epithelial ovarian cancer is an intractable cancer and the overall five-year survival rate is approximately 40 to 50%, clinically effective molecular-targeted therapeutics to treat ovarian cancer has not been available thus far. Recent progress of massively parallel sequencing technologies has been enabling us to identify substantial number of genomic aberrations including somatic mutations, indels and translocations in variable cancer types exemplified by epithelial ovarian cancer and non-small cell lung cancer. However, it is still very difficult to identify a ‘driver’ gene, which is functionally relevant for cancer growth, from hundreds of mutations that are usually found from a single cancer sample of an individual patient. An in vitro cultured cell line, which is originated from a clinical sample, can be utilized to assess functions of the genes that are identified to have somatic aberrations in the paired clinical tumor. We have been establishing multiple ovarian cancer cell lines derived from clinical samples and analyzing pairs of the cell lines and clinical samples with exon-capture sequencing. The genes, which are somatically mutated and shared in a pair of cell line and clinical sample, are targeted with RNA interference in the cell line, and subsequently the effect on cell proliferation and survival is examined. As such, a driver mutation for an individual cancer can be identified by a set of experimental perturbations. Identified driver mutations would be then validated with publicly available databases and with clinical archive samples. As a proof-of-principle, somatic mutations of PIK3CA and KRAS were detected as drivers to promote cell proliferation of a carcinosarcoma. We believe this approach can increase an opportunity to identify molecular targets in ovarian cancer therapeutics. Citation Format: Seiichi Mori, Takako Yokomizo, Takeshi Fujiwara, Osamu Goto, Haruko Iwase, Kazuyoshi Kato, Tokuichi Kawaguchi, Tetsuo Noda. Systematic functional assessment of driver mutations for individual ovarian cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2014-1543