Abstract 4171: Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response

Abstract

Abstract Large cancer genome profiling efforts are releasing pan-molecular information for large numbers of patients into the public domain. A large proportion of novel oncogenic events discovered through these efforts are deleterious to gene/protein function. Recent clinical data from PARP inhibitors has highlighted the promise of tumor cell selective killing where loss of function of a tumor suppressor gene, in this case BRCA, results in a targetable dependency. We sought to take advantage of the pan-molecular information in these data sets to identify molecular patterns indicative of the mutually exclusive loss of function expected between synthetic lethal gene pairs. We have developed a toolkit comprising BiSEp (BImodality Subsetting ExPression) and SLinG (Synthetic Lethality in Genomics) with which we are able to identify instances of genetic and/or gene expression loss that are mutually exclusive between functionally redundant genes. We demonstrate the power of this toolkit to identify known synthetic lethal gene pairings from cancer literature and yeast based screens. We have also revealed a number of novel candidate synthetic lethal gene pairings, and highlight the value of paired biomarkers provided through this approach to select disease models for hypothesis testing. Through a further adaptation, BEEP (Bimodal Expression Exclusive with Pharmacology), we have gone on to identify biomarkers of response to a number of clinical drug candidates. Here we present these algorithms and supporting data for a number of candidate target and biomarker hypotheses discovered, and discuss rationale for their application in cancer drug research. Citation Format: Jonathan R. Dry, Mark Wappett, Ron Yang. Integrating pan-molecular data sets by bimodality to nominate synthetic lethal gene pairs and biomarkers of drug response. [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 4171. doi:10.1158/1538-7445.AM2014-4171