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Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Dylan M. Glubb _, Sharon E. Johnatty, Michael C.J. Quinn, Tracy A. O’Mara, Jonathan P. Tyrer, Bo Gao, Peter A. Fasching, Matthias W. Beckmann, Diether Lambrechts, Ignace Vergote, Digna R. Velez Edwards, Alicia Beeghly-Fadiel, Javier Benitez, Maria J. Garcia, Marc T. Goodman, Pamela J. Thompson, Thilo Dörk, Matthias Dürst, Francesmary Modungo, Kirsten Moysich, Florian Heitz, Andreas du Bois, Jacobus Pfisterer, Peter Hillemanns, On behalf of the AGO Study Group, Beth Y. Karlan, Jenny Lester, Ellen L. Goode, Julie M. Cunningham, Stacey J. Winham, Melissa C. Larson, Bryan M. McCauley, Susanne Krüger Kjær, Allan Jensen, Joellen M. Schildkraut, Andrew Berchuck, Daniel W. Cramer, Kathryn L. Terry, Helga B. Salvesen, Line Bjorge, Penny M. Webb, Peter Grant, Tanja Pejovic, Melissa Moffitt, Claus K. Hogdall, Estrid Hogdall, James Paul, Rosalind Glasspool, Marcus Bernardini, Alicia Tone, David Huntsman, Michelle Woo, AOCS Group, Anna deFazio, Catherine J. Kennedy, Stuart MacGregor, Stuart MacGregor, Georgia Chenevix-Trench

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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.

Author Information

Dylan M. Glubb
Primary Contact  _

Sharon E. Johnatty

Michael C.J. Quinn

Tracy A. O’Mara

Jonathan P. Tyrer

Bo Gao

Peter A. Fasching

Matthias W. Beckmann

Diether Lambrechts

Ignace Vergote

Digna R. Velez Edwards

Alicia Beeghly-Fadiel

Javier Benitez

Maria J. Garcia

Marc T. Goodman

Pamela J. Thompson

Thilo Dörk

Matthias Dürst

Francesmary Modungo

Kirsten Moysich

Florian Heitz

Andreas du Bois

Jacobus Pfisterer

Peter Hillemanns

On behalf of the AGO Study Group

Beth Y. Karlan

Jenny Lester

Ellen L. Goode

Julie M. Cunningham

Stacey J. Winham

Melissa C. Larson

Bryan M. McCauley

Susanne Krüger Kjær

Allan Jensen

Joellen M. Schildkraut

Andrew Berchuck

Daniel W. Cramer

Kathryn L. Terry

Helga B. Salvesen

Line Bjorge

Penny M. Webb

Peter Grant

Tanja Pejovic

Melissa Moffitt

Claus K. Hogdall

Estrid Hogdall

James Paul

Rosalind Glasspool

Marcus Bernardini

Alicia Tone

David Huntsman

Michelle Woo

AOCS Group

Anna deFazio

Catherine J. Kennedy

Stuart MacGregor

Stuart MacGregor

Georgia Chenevix-Trench


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