Article | Published:

Genome-wide significant risk associations for mucinous ovarian carcinoma

Nature Genetics volume 47, pages 888897 (2015) | Download Citation

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Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

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Change history

  • 15 July 2015

    In the version of this article initially published online, three authors’ names were given incorrectly: Xiaoqing Chen as Xiaoqin Chen, Noor Azmi Mat Adenan as Mat Adenan Noor Azmi, and Wlodzimierz Sawicki as Sawicki Wlodzmierz. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement 223175–HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control Consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs).

Author information

Author notes

    • Linda E Kelemen
    •  & Kate Lawrenson

    These authors contributed equally to this work.

Affiliations

  1. Department of Public Health Sciences, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Linda E Kelemen
  2. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Kate Lawrenson
    • , Janet M Lee
    • , Tassja J Spindler
    • , Alice W Lee
    • , Celeste Leigh Pearce
    • , Malcolm C Pike
    • , Susan J Ramus
    • , Anna H Wu
    •  & Simon A Gayther
  3. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Jonathan Tyrer
    • , Patricia Harrington
    • , Honglin Song
    •  & Paul D P Pharoah
  4. Medical College, Xiamen University, Xiamen, China.

    • Qiyuan Li
  5. Department of Medical Oncology, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Qiyuan Li
    • , Ji-Heui Seo
    •  & Matthew L Freedman
  6. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Catherine M Phelan
    • , Jennifer Permuth-Wey
    •  & Thomas A Sellers
  7. Department of Cancer Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Jonathan Beesley
    • , Xiaoqing Chen
    •  & Georgia Chenevix-Trench
  8. Department for Health Evidence, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.

    • Katja K H Aben
    •  & Lambertus A Kiemeney
  9. Comprehensive Cancer Centre the Netherlands, Utrecht, the Netherlands.

    • Katja K H Aben
  10. Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California–Irvine, Irvine, California, USA.

    • Hoda Anton-Culver
    •  & Argyrios Ziogas
  11. Byelorussian Institute for Oncology and Medical Radiology Aleksandrov N.N., Minsk, Belarus.

    • Natalia Antonenkova
  12. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Helen Baker
    • , Joe Dennis
    • , Ed Dicks
    • , Douglas T Easton
    • , Honglin Song
    •  & Paul D P Pharoah
  13. Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick, New Jersey, USA.

    • Elisa V Bandera
  14. Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA.

    • Yukie Bean
    • , Melissa Kellar
    •  & Tanja Pejovic
  15. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.

    • Yukie Bean
    • , Melissa Kellar
    •  & Tanja Pejovic
  16. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany.

    • Matthias W Beckmann
    • , Peter A Fasching
    •  & Alexander Hein
  17. Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Maria Bisogna
    •  & Douglas A Levine
  18. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.

    • Line Bjorge
    • , Camilla Krakstad
    • , Helga B Salvesen
    •  & Ingvild L Tangen
  19. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Line Bjorge
    • , Camilla Krakstad
    • , Helga B Salvesen
    •  & Ingvild L Tangen
  20. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

    • Natalia Bogdanova
    •  & Thilo Dörk
  21. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Louise A Brinton
    • , Bu-Tian Ji
    • , Nicolas Wentzensen
    •  & Hannah Yang
  22. Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Angela Brooks-Wilson
  23. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

    • Angela Brooks-Wilson
  24. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Fiona Bruinsma
    •  & Graham G Giles
  25. Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

    • Ralf Butzow
  26. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

    • Ralf Butzow
    • , Arto Leminen
    • , Heli Nevanlinna
    •  & Liisa M Pelttari
  27. Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

    • Ian G Campbell
  28. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

    • Ian G Campbell
    •  & Melissa C Southey
  29. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

    • Ian G Campbell
  30. Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, UK.

    • Karen Carty
    • , Rosalind Glasspool
    •  & James Paul
  31. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jenny Chang-Claude
    • , Ursula Eilber
    •  & Anja Rudolph
  32. Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Y Ann Chen
    •  & Zhihua Chen
  33. Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.

    • Linda S Cook
  34. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Daniel W Cramer
    • , Elizabeth M Poole
    • , Kathryn L Terry
    •  & Shelley S Tworoger
  35. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Daniel W Cramer
    •  & Kathryn L Terry
  36. Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Julie M Cunningham
  37. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

    • Cezary Cybulski
    • , Jacek Grownwald
    • , Anna Jakubowska
    •  & Jan Lubinski
  38. Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Agnieszka Dansonka-Mieszkowska
    • , Jolanta Kupryjanczyk
    • , Joanna Moes-Sosnowska
    •  & Iwona K Rzepecka
  39. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

    • Jennifer A Doherty
  40. Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte Evang Huyssens-Stiftung Knappschaft, Essen, Germany.

    • Andreas du Bois
    • , Philipp Harter
    •  & Florian Heitz
  41. Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

    • Andreas du Bois
    • , Philipp Harter
    •  & Florian Heitz
  42. Department of Gynecology, Jena University Hospital–Friedrich Schiller University, Jena, Germany.

    • Matthias Dürst
    •  & Ingo B Runnebaum
  43. Faculty of Medicine, University of Southampton, Southampton, UK.

    • Diana Eccles
  44. Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology and Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Robert P Edwards
    • , Joseph L Kelley
    •  & Francesmary Modugno
  45. Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany.

    • Arif B Ekici
  46. Department of Radiation Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Svend Aage Engelholm
  47. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  48. Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Brooke L Fridley
  49. Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
  50. Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.

    • Aleksandra Gentry-Maharaj
    •  & Usha Menon
  51. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.

    • Graham G Giles
  52. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

    • Graham G Giles
  53. Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.

    • Ellen L Goode
  54. Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marc T Goodman
    •  & Pamela J Thompson
  55. Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Marc T Goodman
    •  & Pamela J Thompson
  56. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.

    • Hanis Nazihah Hasmad
    •  & Soo-Hwang Teo
  57. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Michelle A T Hildebrandt
    •  & Xifeng Wu
  58. Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.

    • Peter Hillemanns
  59. Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Estrid Hogdall
  60. Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Centre, Copenhagen, Denmark.

    • Estrid Hogdall
    • , Allan Jensen
    •  & Susanne K Kjaer
  61. Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Claus Hogdall
    • , Susanne K Kjaer
    • , Lene Lundvall
    •  & Lotte Nedergaard
  62. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Satoyo Hosono
  63. Department of Statistical Science, Duke University, Durham, North Carolina, USA.

    • Edwin S Iversen
  64. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Beth Y Karlan
    • , Jenny Lester
    • , Sandra Orsulic
    •  & Christine Walsh
  65. Vesalius Research Center, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  66. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  67. Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.

    • Sandrina Lambrechts
    • , Els Van Nieuwenhuysen
    •  & Ignace Vergote
  68. Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Nhu D Le
  69. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Shashi Lele
    • , Kirsten B Moysich
    •  & Lara Sucheston
  70. College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA.

    • Dong Liang
  71. Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

    • Jolanta Lissowska
  72. Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Karen Lu
  73. Department of Obstetrics and Gynecology, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Leon F A G Massuger
    •  & Anne M van Altena
  74. Department of Preventive Medicine, Kyushu University Faculty of Medical Science, Nagoya, Japan.

    • Keitaro Matsuo
  75. Department of Health Research and Policy–Epidemiology, Stanford University School of Medicine, Stanford, California, USA.

    • Valerie McGuire
    • , Joseph H Rothstein
    • , Weiva Sieh
    •  & Alice S Whittemore
  76. Public Health Ontario, Toronto, Ontario, Canada.

    • John R McLaughlin
  77. Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK.

    • Iain McNeish
  78. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
  79. Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Francesmary Modugno
  80. Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.

    • Steven A Narod
  81. University of Texas School of Public Health, Houston, Texas, USA.

    • Roberta B Ness
  82. Department of Obstetrics and Gynaecology, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

    • Noor Azmi Mat Adenan
    •  & Yin-Ling Woo
  83. Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Kunle Odunsi
  84. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Sara H Olson
    • , Irene Orlow
    •  & Malcolm C Pike
  85. Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Rachel Palmieri Weber
    •  & Joellen M Schildkraut
  86. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

    • Celeste Leigh Pearce
  87. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Elizabeth M Poole
    •  & Shelley S Tworoger
  88. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.

    • Harvey A Risch
  89. Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.

    • Barry Rosen
  90. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Mary Anne Rossing
    •  & Kristine G Wicklund
  91. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Mary Anne Rossing
  92. Duke Cancer Institute, Durham, North Carolina, USA.

    • Joellen M Schildkraut
  93. Praxis für Humangenetik, Wiesbaden, Germany.

    • Ira Schwaab
  94. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Xiao-Ou Shu
    •  & Wei Zheng
  95. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Yurii B Shvetsov
    •  & Lynne R Wilkens
  96. Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK.

    • Nadeem Siddiqui
  97. University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

    • Soo-Hwang Teo
    •  & Yin-Ling Woo
  98. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Robert A Vierkant
  99. Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.

    • Shan Wang-Gohrke
  100. Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.

    • Wlodzimierz Sawicki
  101. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, USA.

    • Andrew Berchuck

Consortia

  1. The Ovarian Cancer Association Consortium

    Australian Cancer Study

    Australian Ovarian Cancer Study Group

Authors

    Contributions

    L.E.K., K. Lawrenson, P.D.P.P., S.A.G. and A.B. wrote the manuscript. C.M.P. and G.C.-T. coordinated and prepared samples for genotyping. L.E.K., K. Lawrenson, J.T. and P.D.P.P. carried out data analysis including imputation, genotype quality control, association analysis, in silico analyses and in vitro analyses. Q.L. and M.L.F. performed the eQTL analysis. The remaining authors contributed samples or technical expertise. All authors read and approved the final version of the manuscript.

    Competing interests

    The author declare no competing financial interests.

    Corresponding author

    Correspondence to Simon A Gayther.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Tables 1–9 and Supplementary Note.

    About this article

    Publication history

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    Accepted

    Published

    DOI

    https://doi.org/10.1038/ng.3336

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