Poster Presentation 25th Lorne Cancer Conference 2013

Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer (#154)

Sally J Davis 1 , Karen E Sheppard 2 , Richard B Pearson 2 , Ian G Campbell 1 , Kylie L Gorringe 1 , Kaylene J Simpson 3
  1. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  2. Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  3. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

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 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 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.
Capitalizing on developments in high-throughput siRNA screening technology, we systematically assessed all genes within regions commonly amplified in high grade serous and endometrioid cancer to identify functional driver genes that may be targeted in the treatment of advanced tumors. Our boutique siRNA library targeting 272 genes located within regions of amplification in primary ovarian cancers was screened across 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.
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.
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 advanced ovarian tumors.