Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer
Purpose: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for ~140,000 deaths annually worldwide. Copy number amplification is frequently associated with activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in regions of amplification in high-grade serous and endometrioid ovarian tumors. Experimental Design: High-throughput siRNA screening was used to systematically assess all genes within regions commonly amplified in high grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene over expression. Results: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2 and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic utility of such genes, particularly URI1 and GAB2, which were significantly associated with survival in two independent tumor cohorts. Conclusions: By taking this integrative approach to target discovery we have streamlined the translation of high-resolution genomic data into pre-clinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of ovarian tumors.