Abstract
Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number amplification is frequently associated with the 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(s) the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in the regions of amplification in high-grade serous and endometrioid ovarian tumors. High-throughput siRNA screening technology 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 overexpression. 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 use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors.
Highlights
Ovarian cancer is associated with the highest mortality rate of all gynecologic malignancies and is identified as the seventh most common cause of cancer-related death for women, with approximately 140,000 deaths annually worldwide [1]
Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be targeted for the treatment of advanced ovarian tumors
We describe the largest systematic functional assessment of genes located in frequently amplified regions of the ovarian tumor genome in an extensive panel of ovarian cancer cell lines that recapitulate the amplifications observed in primary samples
Summary
Ovarian cancer is associated with the highest mortality rate of all gynecologic malignancies and is identified as the seventh most common cause of cancer-related death for women, with approximately 140,000 deaths annually worldwide [1]. This high mortality rate is commonly attributed to the diagnosis of advanced stage disease and is often. Authors' Affiliations: 1Cancer Genetics Laboratory, 2Oncogenic Signaling and Growth Control Program, and 3Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne; and Departments of 4Pathology and 5Biochemistry and Molecular Biology and 6Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
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