RRC ID 44271
Author Davis SJ, Sheppard KE, Pearson RB, Campbell IG, Gorringe KL, Simpson KJ.
Title Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer.
Journal Clin. Cancer Res.
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.
Volume 19(6)
Pages 1411-21
Published 2013-3-15
DOI 10.1158/1078-0432.CCR-12-3433
PII 1078-0432.CCR-12-3433
PMID 23362323
MeSH Adaptor Proteins, Signal Transducing / genetics Carcinoma, Endometrioid / genetics* Carcinoma, Endometrioid / pathology Cell Line, Tumor DNA Copy Number Variations Female Gene Expression Regulation, Neoplastic Humans In Situ Hybridization, Fluorescence Intracellular Signaling Peptides and Proteins / genetics Neoplasm Staging Oligonucleotide Array Sequence Analysis Ovarian Neoplasms / genetics* Ovarian Neoplasms / pathology Polymorphism, Single Nucleotide Prognosis Protein-Serine-Threonine Kinases / genetics Protein-Tyrosine Kinases / genetics RNA, Small Interfering / genetics* RNA, Small Interfering / isolation & purification p21-Activated Kinases / genetics
IF 10.199
Times Cited 21
Human and Animal Cells