1. Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
- Author
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Maria P. Intermaggio, Richard B. Pearson, Kaylene J. Simpson, Anna H. Wu, Usha Menon, Jacobus Pfisterer, Andreas du Bois, David G. Huntsman, Aleksandra Gentry-Maharaj, Sian Fereday, Ian G. Campbell, Nadia Traficante, Jacek Gronwald, David D.L. Bowtell, Kylie L. Gorringe, Jan Lubinski, Joshy George, Karen E. Sheppard, Malcolm C. Pike, Stefan Kommoss, Celeste Leigh Pearce, Susan J. Ramus, Felix Hilpert, Michael S. Anglesio, and Sally J. Davis
- Subjects
Adult ,Cancer Research ,DNA Copy Number Variations ,Cell Survival ,Pyridones ,Kaplan-Meier Estimate ,Biology ,Disease-Free Survival ,Metastasis ,Ovarian tumor ,Young Adult ,Ovarian carcinoma ,Cell Line, Tumor ,medicine ,Carcinoma ,Humans ,Gene Regulatory Networks ,Adaptor Proteins, Signal Transducing ,Aged ,Phosphoinositide-3 Kinase Inhibitors ,Aged, 80 and over ,Ovarian Neoplasms ,Oncogene ,Gene Expression Profiling ,Gene Amplification ,Middle Aged ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Serous fluid ,Pyrimidines ,Oncology ,Multivariate Analysis ,Cancer research ,Female ,Neoplasm Grading ,Ovarian cancer - Abstract
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. Mol Cancer Ther; 14(6); 1495–503. ©2015 AACR.
- Published
- 2015