Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Campbell, Ian × Author: DAVIS, SALLY × Author: Gorringe, Kylie × Author: Sheppard, Karen ×

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    Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
    Davis, SJ ; Sheppard, KE ; Anglesio, MS ; George, J ; Traficante, N ; Fereday, S ; Intermaggio, MP ; Menon, U ; Gentry-Maharaj, A ; Lubinski, J ; Gronwald, J ; Pearce, CL ; Pike, MC ; Wu, A ; Kommoss, S ; Pfisterer, J ; du Bois, A ; Hilpert, F ; Ramus, SJ ; Bowtell, DDL ; Huntsman, DG ; Pearson, RB ; Simpson, KJ ; Campbell, IG ; Gorringe, KL (AMER ASSOC CANCER RESEARCH, 2015-06)
    Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling.
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    Functional Analysis of Genes in Regions Commonly Amplified in High-Grade Serous and Endometrioid Ovarian Cancer
    Davis, SJ ; Sheppard, KE ; Pearson, RB ; Campbell, IG ; Gorringe, KL ; Simpson, KJ (AMER ASSOC CANCER RESEARCH, 2013-03-15)
    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.