Abstract 5123: An integrated genomics approach to identify novel drivers of oncogenic pathway activity in human cancer
Authors: Gatza Michael L. , Kim So Young , Reeves Jason , Lucas Joseph E. , Nevins Joseph R. 
Published: August 2012

Abstract
Human cancers are defined by molecular and clinical heterogeneity. The molecular diversity of human tumors is a significant contributing factor to the inefficiency of current therapeutic regimens and the high failure rate of developing new anti-cancer therapies. One of the major contributing factors to this variability is the enormous diversity and complexity of genome alterations. In order to understand the molecular complexity driving tumor development and to identify novel therapeutic targets to enhance treatment efficacy and overcome therapeutic resistance, we have developed an integrative genomics approach to identify novel drivers of oncogenic pathway activity and applied this strategy to investigate serous ovarian cancer. Since it has been demonstrated that mutations in many different genes can result in the activation of an oncogenic signaling pathway resulting in enhanced cell proliferation and transformation, our analysis focused on regulation of pathway activity rather than the mutation of a single gene. As such, we utilized 18 previously developed and validated gene expression signatures of oncogenic pathway activity as a framework to integrate multiple, disparate forms of genomic data. We first identified 1,020 high-grade, late stage serous ovarian tumors with Affymetrix U133 expression data from multiple published studies and the predicted oncogenic pathway activity was determined for each tumor. Of these tumors, &gt;500 had matched aCGH data which were used to identify statistically significant chromosomal alterations directly and indirectly associated with each pathway. This strategy was validated by identifying associations between pathway activity and copy number alterations of known pathway drivers. We next compiled a dataset of ovarian cancer cell lines with U133 expression data and for which genome-wide shRNA proliferation data was available. These data were used to identify essential genes required for cell viability in pathway-dependent manner. The resulting genes were analyzed by DAVID and GATHER to validate that this strategy identified key pathway components. Finally, by integrating results obtained from the aCGH and shRNA analyses, we identified known and candidate genes associated with oncogenic pathway activity that are required for cell viability and are amplified in human tumors. These analyses have identified alterations of putative and known regulators of pathway activity that often exist independent of each other in human tumors suggesting that examining the mutational status of a single gene is an incomplete measure of pathway activity and that this strategy is able to identify novel regulators, and therefore potential therapeutic targets, of oncogenic signaling pathways required for tumor proliferation. Additional studies are underway to investigate the role identified candidate genes play in pathway activity and tumor proliferation.
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 5123. doi:1538-7445.AM2012-5123