RRC ID 65431
Author 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 DD, Huntsman DG, Pearson RB, Simpson KJ, Campbell IG, Gorringe KL.
Title Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition.
Journal Mol Cancer Ther
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.
Volume 14(6)
Pages 1495-503
Published 2015-6-1
DOI 10.1158/1535-7163.MCT-15-0039
PII 1535-7163.MCT-15-0039
PMID 25852062
MeSH Adaptor Proteins, Signal Transducing / genetics* Adaptor Proteins, Signal Transducing / metabolism Adult Aged Aged, 80 and over Cell Line, Tumor Cell Survival / drug effects Cell Survival / genetics Cystadenocarcinoma, Serous / genetics* Cystadenocarcinoma, Serous / metabolism Cystadenocarcinoma, Serous / therapy DNA Copy Number Variations Disease-Free Survival Female Gene Amplification Gene Expression Profiling Gene Expression Regulation, Neoplastic* Gene Regulatory Networks Humans Kaplan-Meier Estimate Middle Aged Multivariate Analysis Neoplasm Grading Ovarian Neoplasms / genetics* Ovarian Neoplasms / metabolism Ovarian Neoplasms / therapy Phosphoinositide-3 Kinase Inhibitors* Pyridones / pharmacology* Pyrimidines / pharmacology* Young Adult
IF 5.615
Human and Animal Cells JHOC-5(RCB1520) JHOC-7(RCB1688) JHOC-9(RCB2226) JHOM-1(RCB1676) JHOS-3(RCB1546)