Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition.
| Title: | Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition. |
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| Authors: | Davis SJ; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.; Sheppard KE; Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Anglesio MS; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; George J; Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.; Traficante N; Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.; Fereday S; Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.; Intermaggio MP; Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.; Menon U; Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom.; Gentry-Maharaj A; Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom.; Lubinski J; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.; Gronwald J; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.; Pearce CL; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.; Pike MC; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.; Wu A; Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.; Kommoss S; Department of Gynecology and Obstetrics, Tuebingen University, Tuebingen, Germany.; Pfisterer J; Department of Gynecology and Obstetrics, Kiel University, Kiel, Germany.; du Bois A; Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Essen, Germany.; Hilpert F; University Hospital Schleswig-Holstein, Kiel, Germany.; Ramus SJ; Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.; Bowtell DD; Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.; Huntsman DG; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Pearson RB; Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Simpson KJ; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.; Campbell IG; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Gorringe KL; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. kylie.gorringe@petermac.org. |
| Source: | Molecular cancer therapeutics [Mol Cancer Ther] 2015 Jun; Vol. 14 (6), pp. 1495-503. Date of Electronic Publication: 2015 Apr 07. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| MeSH Terms: | Gene Expression Regulation, Neoplastic* ; Phosphoinositide-3 Kinase Inhibitors*; Adaptor Proteins, Signal Transducing/*genetics ; Cystadenocarcinoma, Serous/*genetics ; Ovarian Neoplasms/*genetics ; Pyridones/*pharmacology ; Pyrimidines/*pharmacology; Adaptor Proteins, Signal Transducing/metabolism ; Cell Survival/drug effects ; Cell Survival/genetics ; Cystadenocarcinoma, Serous/metabolism ; Cystadenocarcinoma, Serous/therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/therapy ; Adult ; Aged ; Aged, 80 and over ; Cell Line, Tumor ; DNA Copy Number Variations ; Disease-Free Survival ; Female ; Gene Amplification ; Gene Expression Profiling ; Gene Regulatory Networks ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Multivariate Analysis ; Neoplasm Grading ; Young Adult |
| 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.; (©2015 American Association for Cancer Research.) |
| Comments: | Erratum in: Mol Cancer Ther. 2017 Mar;16(3):551. doi: 10.1158/1535-7163.MCT-17-0067.. (PMID: 28258085) |
| Substance Nomenclature: | 0 (2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one); 0 (Adaptor Proteins, Signal Transducing); 0 (GAB2 protein, human); 0 (Phosphoinositide-3 Kinase Inhibitors); 0 (Pyridones); 0 (Pyrimidines) |
| Entry Date(s): | Date Created: 20150409 Date Completed: 20160412 Latest Revision: 20200930 |
| Update Code: | 20260130 |
| DOI: | 10.1158/1535-7163.MCT-15-0039 |
| PMID: | 25852062 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't