Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Stacey J Winham; Ailith Pirie; Yian Ann Chen; Melissa C Larson; Zachary C Fogarty; Madalene A Earp; Hoda Anton-Culver; Elisa V Bandera; Daniel Cramer; Jennifer A Doherty; Marc T Goodman; Jacek Gronwald; Beth Y Karlan; Susanne K Kjaer; Douglas A Levine; Usha Menon; Roberta B Ness; Celeste L Pearce; Tanja Pejovic; Mary Anne Rossing; Nicolas Wentzensen; Yukie T Bean; Maria Bisogna; Louise A Brinton; Michael E Carney; Julie M Cunningham; Cezary Cybulski; Anna deFazio; Ed M Dicks; Robert P Edwards; Simon A Gayther; Aleksandra Gentry-Maharaj; Martin Gore; Edwin S Iversen; Allan Jensen; Sharon E Johnatty; Jenny Lester; Hui-Yi Lin; Jolanta Lissowska; Jan Lubinski; Janusz Menkiszak; Francesmary Modugno; Kirsten B Moysich; Irene Orlow; Malcolm C Pike; Susan J Ramus; Honglin Song; Kathryn L Terry; Pamela J Thompson; Jonathan P Tyrer; David J van den Berg; Robert A Vierkant; Allison F Vitonis; Christine Walsh; Lynne R Wilkens; Anna H Wu; Hannah Yang; Argyrios Ziogas; Andrew Berchuck; Georgia Chenevix-Trench; Joellen M Schildkraut; Jennifer Permuth-Wey; Catherine M Phelan; Paul D P Pharoah; Brooke L Fridley; Thomas A Sellers; Ellen L Goode; Australian Ovarian Cancer Study Group

doi:10.1158/1055-9965.EPI-15-0240

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Journal article

Open access

Peer reviewed

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Stacey J Winham, Ailith Pirie, Yian Ann Chen, Melissa C Larson, Zachary C Fogarty, Madalene A Earp, Hoda Anton-Culver, Elisa V Bandera, Daniel Cramer, Jennifer A Doherty, …

Cancer epidemiology, biomarkers & prevention, Vol.25(3), pp.446-454

03/2016

DOI: https://doi.org/10.1158/1055-9965.EPI-15-0240

PMCID: PMC4779669

PMID: 26747452

Abstract

Exome

Female

Genotype

Humans

Middle Aged

Ovarian Neoplasms - genetics

Ovarian Neoplasms - mortality

Survival Rate

While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.

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Title: Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer
Creators: Stacey J Winham - Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
Ailith Pirie - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Yian Ann Chen - Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Melissa C Larson - Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
Zachary C Fogarty - Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
Madalene A Earp - Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota
Hoda Anton-Culver - Department of Epidemiology, University of California Irvine, Irvine, California
Elisa V Bandera - Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey
Daniel Cramer - Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
Jennifer A Doherty - Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
Marc T Goodman - Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Jacek Gronwald - Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Beth Y Karlan - Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Susanne K Kjaer - Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Douglas A Levine - Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Usha Menon - Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom
Roberta B Ness - The University of Texas School of Public Health, Houston, Texas
Celeste L Pearce - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Tanja Pejovic - Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
Mary Anne Rossing - Department of Epidemiology, University of Washington, Seattle, Washington. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
Nicolas Wentzensen - Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland
Yukie T Bean - Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
Maria Bisogna - Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Louise A Brinton - Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland
Michael E Carney - Department of Obstectrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii
Julie M Cunningham - Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota
Cezary Cybulski - Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical Academy, Szczecin, Poland
Anna deFazio - Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia. Center for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia
Ed M Dicks - Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
Robert P Edwards - Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Simon A Gayther - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Aleksandra Gentry-Maharaj - Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom
Martin Gore - Gynecological Oncology Unit, The Royal Marsden Hospital, London, United Kingdom
Edwin S Iversen - Department of Statistical Science, Duke University, Durham, North Carolina
Allan Jensen - Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
Sharon E Johnatty - Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Jenny Lester - Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Hui-Yi Lin - Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Jolanta Lissowska - Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
Jan Lubinski - Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Janusz Menkiszak - Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
Francesmary Modugno - Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania. Womens Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
Kirsten B Moysich - Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
Irene Orlow - Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
Malcolm C Pike - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
Susan J Ramus - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Honglin Song - Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
Kathryn L Terry - Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
Pamela J Thompson - Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Jonathan P Tyrer - Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
David J van den Berg - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Robert A Vierkant - Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
Allison F Vitonis - Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Christine Walsh - Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Lynne R Wilkens - Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
Anna H Wu - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Hannah Yang - Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland
Argyrios Ziogas - Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, California
Andrew Berchuck - Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina
Georgia Chenevix-Trench
Joellen M Schildkraut - Public Health Services, University of Virginia, Charlottesville, Virginia
Jennifer Permuth-Wey - Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Catherine M Phelan - Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Paul D P Pharoah - Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
Brooke L Fridley - Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Kansas Cancer Center, Kansas City, Kansas
Thomas A Sellers - Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Ellen L Goode - Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota. egoode@mayo.edu
Australian Ovarian Cancer Study Group
Publication Details: Cancer epidemiology, biomarkers & prevention, Vol.25(3), pp.446-454
Date published: 03/2016
Grant note: R03 CA113148 / NCI NIH HHS N01 CN025403 / NCI NIH HHS K22-CA138563 / NCI NIH HHS A10119 / Cancer Research UK R01-CA95023 / NCI NIH HHS Medical Research Council R01-CA122443 / NCI NIH HHS K22 CA138563 / NCI NIH HHS K12HD065987 / NICHD NIH HHS M01-RR000056 / NCRR NIH HHS R03 CA115195 / NCI NIH HHS P30 CA071789 / NCI NIH HHS R01 CA058598 / NCI NIH HHS M01 RR000056 / NCRR NIH HHS P01 CA017054 / NCI NIH HHS C490/A10124 / Cancer Research UK R01 CA61107 / NCI NIH HHS N01-CN025403 / NCI NIH HHS N01-CN-55424 / NCI NIH HHS P30-CA14089 / NCI NIH HHS P50 CA105009 / NCI NIH HHS R03-CA115195 / NCI NIH HHS R01 CA-149429 / NCI NIH HHS R01 CA054419 / NCI NIH HHS R01 CA095023 / NCI NIH HHS K07 CA080668 / NCI NIH HHS R01-CA61132 / NCI NIH HHS P50-CA105009 / NCI NIH HHS N01-PC-67001 / NCI NIH HHS R01 CA178535 / NCI NIH HHS K12 HD065987 / NICHD NIH HHS R01 CA122443 / NCI NIH HHS K07-CA080668 / NCI NIH HHS R01-CA54419 / NCI NIH HHS U19-CA148112 / NCI NIH HHS A10124 / Cancer Research UK C490/A10119 / Cancer Research UK R01-CA126841 / NCI NIH HHS P30 CA015083 / NCI NIH HHS K07 CA095666 / NCI NIH HHS R01 CA149429 / NCI NIH HHS P30-CA072720 / NCI NIH HHS 10124 / Cancer Research UK U19 CA148112 / NCI NIH HHS P50 CA159981 / NCI NIH HHS R01-CA58598 / NCI NIH HHS UL1 TR000124 / NCATS NIH HHS N01 PC067010 / NCI NIH HHS P01-CA17054 / NCI NIH HHS UL1TR000124 / NCATS NIH HHS N01-PC67010 / NCI NIH HHS P30 CA008748 / NCI NIH HHS P50-CA159981 / NCI NIH HHS P50 CA136393 / NCI NIH HHS P30-CA15083 / NCI NIH HHS R01 CA126841 / NCI NIH HHS R03-CA113148 / NCI NIH HHS P30 CA014089 / NCI NIH HHS P30 CA072720 / NCI NIH HHS
Academic Unit: Cancer Epidemiology and Health Outcomes
Language: English
Resource Type: Journal article
Identifiers: 991031665461504646