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Abstract
Purpose: 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.
Experimental Design:
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.
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 use of such
genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts.
Conclusion: 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.
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