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Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci
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Abstract
Dylan M. Glubb1, Sharon E. Johnatty1, Michael C.J. Quinn1, Tracy A. O’Mara1, Jonathan P. Tyrer2, Bo Gao3,4, Peter A. Fasching5,6, Matthias W. Beckmann6, Diether Lambrechts7,8, Ignace Vergote9, Digna R. Velez Edwards10, Alicia Beeghly-Fadiel11, Javier Benitez12, Maria J. Garcia12, Marc T. Goodman13,14, Pamela J. Thompson13,14, Thilo Dörk15, Matthias Dürst16, Francesmary Modungo17,18,19, Kirsten Moysich20, Florian Heitz21,22, Andreas du Bois21,22, Jacobus Pfisterer23, Peter Hillemanns24 On behalf of the AGO Study Group, Beth Y. Karlan25, Jenny Lester25, Ellen L. Goode26, Julie M. Cunningham27, Stacey J. Winham26, Melissa C. Larson26, Bryan M. McCauley26, Susanne Krüger Kjær28,29, Allan Jensen29, Joellen M. Schildkraut30, Andrew Berchuck31, Daniel W. Cramer32, Kathryn L. Terry32,33, Helga B. Salvesen34,35, Line Bjorge34,35, Penny M. Webb36, Peter Grant37, Tanja Pejovic38,39, Melissa Moffitt38,39, Claus K. Hogdall28, Estrid Hogdall28,29, James Paul40, Rosalind Glasspool40, Marcus Bernardini41, Alicia Tone41, David Huntsman42,43, Michelle Woo44, AOCS Group1,45, Anna deFazio4,46, Catherine J. Kennedy4,46, Paul D.P. Pharoah2,47, Stuart MacGregor1 and Georgia Chenevix-Trench1
1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
2 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
3 Crown Princess Mary Cancer Care Centre, Westmead Hospital, Sydney, NSW, Australia
4 Center for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
5 University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, CA, USA
6 University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
7 Vesalius Research Center, VIB, Leuven, Belgium
8 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
9 Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
10 Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN, USA
11 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
12 Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain
13 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
14 Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
15 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
16 Department of Gynaecology, University of Jena, Jena, Germany
17 Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
18 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
19 Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA
20 Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY, USA
21 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany
22 Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
23 Zentrum für Gynäkologische Onkologie, Kiel, Germany
24 Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
25 Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
26 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
27 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
28 Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
29 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
30 Department of Public Health Sciences, The University of Virginia, Charlottesville, VA, USA
31 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
32 Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
33 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
34 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
35 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
36 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
37 Gynaecological Oncology Department, Mercy Hospital for Women, Melbourne, VIC, Australia
38 Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA
39 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
40 Beatson West of Scotland Cancer Centre, Glasgow, UK
41 Division of Gynecologic Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
42 British Columbia’s Ovarian Cancer Research (OVCARE) Program, Vancouver General Hospital, BC Cancer Agency and University of British Columbia, British Columbia, Canada
43 Departments of Pathology and Laboratory Medicine, Obstetrics and Gynaecology and Molecular Oncology, The University of British Columbia, Vancouver, British Columbia, Canada
44 British Columbia’s Ovarian Cancer Research (OVCARE) Program, Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
45 Peter MacCallum Cancer Center, The University of Melbourne, Australia
46 Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia
47 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
Correspondence to:
Georgia Chenevix-Trench, email:
Keywords: ovarian cancer outcome; genetic association; gene regulation; meta-analysis
Received: March 10, 2017 Accepted: April 27, 2017 Published: June 15, 2017
Abstract
We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.
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