title: Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition.
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.
authors: Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Sally J
authors: SJ
authors: Davis
authors: 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.
authors: Karen E
authors: KE
authors: Sheppard
authors: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Michael S
authors: MS
authors: Anglesio
authors: Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Joshy
authors: J
authors: George
authors: Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Nadia
authors: N
authors: Traficante
authors: Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Sian
authors: S
authors: Fereday
authors: Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors: Maria P
authors: MP
authors: Intermaggio
authors: Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom.
authors: Usha
authors: U
authors: Menon
authors: Gynaecological Cancer Research Centre, Women's Cancer, University College London, Institute for Women's Health, London, United Kingdom.
authors: Aleksandra
authors: A
authors: Gentry-Maharaj
authors: Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
authors: Jan
authors: J
authors: Lubinski
authors: Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
authors: Jacek
authors: J
authors: Gronwald
authors: Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
authors: Celeste Leigh
authors: CL
authors: Pearce
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Malcolm C
authors: MC
authors: Pike
authors: Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors: Anna
authors: A
authors: Wu
authors: Department of Gynecology and Obstetrics, Tuebingen University, Tuebingen, Germany.
authors: Stefan
authors: S
authors: Kommoss
authors: Department of Gynecology and Obstetrics, Kiel University, Kiel, Germany.
authors: Jacobus
authors: J
authors: Pfisterer
authors: Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK), Essen, Germany.
authors: Andreas
authors: A
authors: du Bois
authors: University Hospital Schleswig-Holstein, Kiel, Germany.
authors: Felix
authors: F
authors: Hilpert
authors: Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors: Susan J
authors: SJ
authors: Ramus
authors: Cancer Genetics and Genomics Laboratory and Australian Ovarian Cancer Study, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: David D L
authors: DD
authors: Bowtell
authors: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: David G
authors: DG
authors: Huntsman
authors: 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.
authors: Richard B
authors: RB
authors: Pearson
authors: 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.
authors: Kaylene J
authors: KJ
authors: Simpson
authors: 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.
authors: Ian G
authors: IG
authors: Campbell
authors: 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.
authors: Kylie L
authors: KL
authors: Gorringe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines