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Genome-wide significant risk associations for mucinous ovarian carcinoma

Nature Genetics volume 47, pages 888–897 (2015)Cite this article

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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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Figure 1: Manhattan plots showing association.
Figure 2: The epigenetic landscape of MOC risk-associated regions.
Figure 3: eQTLs in MOC risk-associated regions.
Figure 4: 3C analysis of the 2q31.1 region containing HOXD9 performed in the EFO-27 MOC cell line.
Figure 5: Modeling the effects of HOXD9 overexpression in two in vitro models of MOC.

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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.

References

  1. Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).

    Article  CAS  Google Scholar 

  2. Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    Article  CAS  Google Scholar 

  3. Walsh, T. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc. Natl. Acad. Sci. USA 108, 18032–18037 (2011).

    Article  CAS  Google Scholar 

  4. Lynch, H.T. et al. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies. Cancer 56, 939–951 (1985).

    Article  CAS  Google Scholar 

  5. Lynch, H.T., Conway, T. & Lynch, J. Hereditary ovarian cancer. Pedigree studies, Part II. Cancer Genet. Cytogenet. 53, 161–183 (1991).

    Article  CAS  Google Scholar 

  6. Boyd, J. & Rubin, S.C. Hereditary ovarian cancer: molecular genetics and clinical implications. Gynecol. Oncol. 64, 196–206 (1997).

    Article  CAS  Google Scholar 

  7. Narod, S.A. et al. Hereditary and familial ovarian cancer in southern Ontario. Cancer 74, 2341–2346 (1994).

    Article  CAS  Google Scholar 

  8. Risch, H.A. et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J. Natl. Cancer Inst. 98, 1694–1706 (2006).

    Article  CAS  Google Scholar 

  9. Song, H. et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996–1000 (2009).

    Article  CAS  Google Scholar 

  10. Goode, E.L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874–879 (2010).

    Article  CAS  Google Scholar 

  11. Bolton, K.L. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42, 880–884 (2010).

    Article  CAS  Google Scholar 

  12. Pharoah, P.D. et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat. Genet. 45, 362–370 (2013).

    Article  CAS  Google Scholar 

  13. Bojesen, S.E. et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat. Genet. 45, 371–384 (2013).

    Article  CAS  Google Scholar 

  14. Permuth-Wey, J. et al. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat. Commun. 4, 1627 (2013).

    Article  Google Scholar 

  15. Couch, F.J. et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 9, e1003212 (2013).

    Article  CAS  Google Scholar 

  16. Chen, K. et al. Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women. Nat. Commun. 5, 4682 (2014).

    Article  CAS  Google Scholar 

  17. Kuchenbaecker, K.B. et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat. Genet. 47, 164–171 (2015).

    Article  CAS  Google Scholar 

  18. Vaughan, S. et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer 11, 719–725 (2011).

    Article  CAS  Google Scholar 

  19. Risch, H.A., Marrett, L.D., Jain, M. & Howe, G.R. Differences in risk factors for epithelial ovarian cancer by histologic type. Results of a case-control study. Am. J. Epidemiol. 144, 363–372 (1996).

    Article  CAS  Google Scholar 

  20. Pearce, C.L. et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 13, 385–394 (2012).

    Article  Google Scholar 

  21. Faber, M.T. et al. Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer Causes Control 24, 989–1004 (2013).

    Article  Google Scholar 

  22. Alsop, K. et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 30, 2654–2663 (2012).

    Article  CAS  Google Scholar 

  23. Köbel, M. et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 5, e232 (2008).

    Article  Google Scholar 

  24. Gilks, C.B. et al. Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum. Pathol. 39, 1239–1251 (2008).

    Article  CAS  Google Scholar 

  25. Tavassoulu,, F.A. & Devilee, P. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs (IARC Press, 2003).

  26. Seidman, J.D., Kurman, R.J. & Ronnett, B.M. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am. J. Surg. Pathol. 27, 985–993 (2003).

    Article  Google Scholar 

  27. Ronnett, B.M. et al. Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior. Hum. Pathol. 35, 949–960 (2004).

    Article  Google Scholar 

  28. Ronnett, B.M. et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei.” Am. J. Surg. Pathol. 19, 1390–1408 (1995).

    Article  CAS  Google Scholar 

  29. Lee, K.R. & Young, R.H. The distinction between primary and metastatic mucinous carcinomas of the ovary: gross and histologic findings in 50 cases. Am. J. Surg. Pathol. 27, 281–292 (2003).

    Article  Google Scholar 

  30. Yemelyanova, A.V., Vang, R., Judson, K., Wu, L.S. & Ronnett, B.M. Distinction of primary and metastatic mucinous tumors involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification. Am. J. Surg. Pathol. 32, 128–138 (2008).

    Article  Google Scholar 

  31. Hart, W.R. Mucinous tumors of the ovary: a review. Int. J. Gynecol. Pathol. 24, 4–25 (2005).

    PubMed  Google Scholar 

  32. Cuatrecasas, M., Villanueva, A., Matias-Guiu, X. & Prat, J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer 79, 1581–1586 (1997).

    Article  CAS  Google Scholar 

  33. Pieretti, M. et al. Heterogeneity of ovarian cancer: relationships among histological group, stage of disease, tumor markers, patient characteristics, and survival. Cancer Invest. 20, 11–23 (2002).

    Article  Google Scholar 

  34. Ichikawa, Y. et al. Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors. Cancer Res. 54, 33–35 (1994).

    CAS  PubMed  Google Scholar 

  35. Feeley, K.M. & Wells, M. Precursor lesions of ovarian epithelial malignancy. Histopathology 38, 87–95 (2001).

    Article  CAS  Google Scholar 

  36. Heinzelmann-Schwarz, V.A. et al. A distinct molecular profile associated with mucinous epithelial ovarian cancer. Br. J. Cancer 94, 904–913 (2006).

    Article  CAS  Google Scholar 

  37. Marquez, R.T. et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin. Cancer Res. 11, 6116–6126 (2005).

    Article  CAS  Google Scholar 

  38. Vogelstein, B. et al. Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319, 525–532 (1988).

    Article  CAS  Google Scholar 

  39. Shen, H. et al. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat. Commun. 4, 1628 (2013).

    Article  Google Scholar 

  40. Kelemen, L.E. & Kobel, M. Mucinous carcinomas of the ovary and colorectum: different organ, same dilemma. Lancet Oncol. 12, 1071–1080 (2011).

    Article  Google Scholar 

  41. Chen, J.M., Ferec, C. & Cooper, D.N. A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants. Hum. Genet. 120, 301–333 (2006).

    Article  CAS  Google Scholar 

  42. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  43. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  44. Brown, C.D., Mangravite, L.M. & Engelhardt, B.E. Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs. PLoS Genet. 9, e1003649 (2013).

    Article  CAS  Google Scholar 

  45. Li, H., Huang, C.J. & Choo, K.B. Expression of homeobox genes in cervical cancer. Gynecol. Oncol. 84, 216–221 (2002).

    Article  CAS  Google Scholar 

  46. Tabuse, M. et al. Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells. Mol. Cancer 10, 60 (2011).

    Article  CAS  Google Scholar 

  47. Laury, A.R. et al. PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma. Am. J. Surg. Pathol. 34, 627–635 (2010).

    PubMed  Google Scholar 

  48. Laury, A.R. et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am. J. Surg. Pathol. 35, 816–826 (2011).

    Article  Google Scholar 

  49. Cheung, H.W. et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. Proc. Natl. Acad. Sci. USA 108, 12372–12377 (2011).

    Article  CAS  Google Scholar 

  50. Muratovska, A., Zhou, C., He, S., Goodyer, P. & Eccles, M.R. Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22, 7989–7997 (2003).

    Article  Google Scholar 

  51. Di Palma, T., Lucci, V., de Cristofaro, T., Filippone, M.G. & Zannini, M. A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells. BMC Cancer 14, 292 (2014).

    Article  Google Scholar 

  52. Duggal, P. et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann. Intern. Med. 158, 235–245 (2013).

    Article  Google Scholar 

  53. Ochi, H. et al. IL-28B predicts response to chronic hepatitis C therapy—fine-mapping and replication study in Asian populations. J. Gen. Virol. 92, 1071–1081 (2011).

    Article  CAS  Google Scholar 

  54. Key, F.M. et al. Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon λ4 (IFNL4). PLoS Genet. 10, e1004681 (2014).

    Article  Google Scholar 

  55. Urban, T.J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).

    Article  CAS  Google Scholar 

  56. Pejovic, T. Genetic changes in ovarian cancer. Ann. Med. 27, 73–78 (1995).

    Article  CAS  Google Scholar 

  57. Houlston, R.S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat. Genet. 42, 973–977 (2010).

    Article  CAS  Google Scholar 

  58. Michailidou, K. et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat. Genet. 45, 353–361 (2013).

    Article  CAS  Google Scholar 

  59. Eeles, R.A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391 (2013).

    Article  CAS  Google Scholar 

  60. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    Article  CAS  Google Scholar 

  61. Permuth-Wey, J. et al. LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer. Cancer Res. 71, 3896–3903 (2011).

    Article  CAS  Google Scholar 

  62. Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2012).

    Article  CAS  Google Scholar 

  63. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  Google Scholar 

  64. Xing, G., Lin, C.Y., Wooding, S.P. & Xing, C. Blindly using Wald's test can miss rare disease-causal variants in case-control association studies. Ann. Hum. Genet. 76, 168–177 (2012).

    Article  Google Scholar 

  65. Coetzee, S.G. et al. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci. Hum. Mol. Genet. doi:10.1093/hmg/ddv101 (24 March 2015).

  66. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Google Scholar 

  67. Li, Q. et al. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci. Cell 152, 633–641 (2013).

    Article  CAS  Google Scholar 

  68. Li, Q. et al. Expression QTL–based analyses reveal candidate causal genes and loci across five tumor types. Hum. Mol. Genet. 23, 5294–5302 (2014).

    Article  CAS  Google Scholar 

  69. Kunzmann, R. & Holzel, F. Karyotype alterations in human ovarian carcinoma cells during long-term cultivation and nude mouse passage. Cancer Genet. Cytogenet. 28, 201–212 (1987).

    Article  CAS  Google Scholar 

  70. Li, N.F. et al. A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitro. Lab. Invest. 84, 923–931 (2004).

    Article  Google Scholar 

  71. Pomerantz, M.M. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).

    Article  CAS  Google Scholar 

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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

  1. Linda E Kelemen, Kate Lawrenson and Andrew Berchuck: These authors contributed equally to this work.

Authors and 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. Department of Oncology, Centre for Cancer Genetic Epidemiology, 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. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, 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. Department of Surgery, Gynecology Service, 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. Department of Clinical Science, Centre for Cancer Biomarkers, 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. Research Division, Cancer Genetics Laboratory, 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. Department of Genetics and Pathology, International Hereditary Cancer Center, 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, Division of Gynecologic Oncology and Ovarian Cancer Center of Excellence, Gynecology and Reproductive Sciences, 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. Department of Women's Cancer, Gynaecological Cancer Research Centre, 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. Department of Biomedical Sciences, Community and Population Health Research Institute, 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. Department of Oncology, Laboratory for Translational Genetics, 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. Division of Public Health Sciences, Program in Epidemiology, 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

The Ovarian Cancer Association Consortium

  • Linda E Kelemen
  • , Kate Lawrenson
  • , Jonathan Tyrer
  • , Qiyuan Li
  • , Janet M Lee
  • , Ji-Heui Seo
  • , Catherine M Phelan
  • , Jonathan Beesley
  • , Xiaoqing Chen
  • , Tassja J Spindler
  • , Katja K H Aben
  • , Hoda Anton-Culver
  • , Natalia Antonenkova
  • , Australian Cancer Study
  • , Australian Ovarian Cancer Study Group
  • , Helen Baker
  • , Elisa V Bandera
  • , Yukie Bean
  • , Matthias W Beckmann
  • , Maria Bisogna
  • , Line Bjorge
  • , Natalia Bogdanova
  • , Louise A Brinton
  • , Angela Brooks-Wilson
  • , Fiona Bruinsma
  • , Ralf Butzow
  • , Ian G Campbell
  • , Karen Carty
  • , Jenny Chang-Claude
  • , Y Ann Chen
  • , Zhihua Chen
  • , Linda S Cook
  • , Daniel W Cramer
  • , Julie M Cunningham
  • , Cezary Cybulski
  • , Agnieszka Dansonka-Mieszkowska
  • , Joe Dennis
  • , Ed Dicks
  • , Jennifer A Doherty
  • , Thilo Dörk
  • , Andreas du Bois
  • , Matthias Dürst
  • , Diana Eccles
  • , Douglas T Easton
  • , Robert P Edwards
  • , Ursula Eilber
  • , Arif B Ekici
  • , Svend Aage Engelholm
  • , Peter A Fasching
  • , Brooke L Fridley
  • , Yu-Tang Gao
  • , Aleksandra Gentry-Maharaj
  • , Graham G Giles
  • , Rosalind Glasspool
  • , Ellen L Goode
  • , Marc T Goodman
  • , Jacek Grownwald
  • , Patricia Harrington
  • , Philipp Harter
  • , Hanis Nazihah Hasmad
  • , Alexander Hein
  • , Florian Heitz
  • , Michelle A T Hildebrandt
  • , Peter Hillemanns
  • , Estrid Hogdall
  • , Claus Hogdall
  • , Satoyo Hosono
  • , Edwin S Iversen
  • , Anna Jakubowska
  • , Allan Jensen
  • , Bu-Tian Ji
  • , Beth Y Karlan
  • , Melissa Kellar
  • , Joseph L Kelley
  • , Lambertus A Kiemeney
  • , Camilla Krakstad
  • , Susanne K Kjaer
  • , Jolanta Kupryjanczyk
  • , Diether Lambrechts
  • , Sandrina Lambrechts
  • , Nhu D Le
  • , Alice W Lee
  • , Shashi Lele
  • , Arto Leminen
  • , Jenny Lester
  • , Douglas A Levine
  • , Dong Liang
  • , Jolanta Lissowska
  • , Karen Lu
  • , Jan Lubinski
  • , Lene Lundvall
  • , Leon F A G Massuger
  • , Keitaro Matsuo
  • , Valerie McGuire
  • , John R McLaughlin
  • , Iain McNeish
  • , Usha Menon
  • , Francesmary Modugno
  • , Joanna Moes-Sosnowska
  • , Kirsten B Moysich
  • , Steven A Narod
  • , Lotte Nedergaard
  • , Roberta B Ness
  • , Heli Nevanlinna
  • , Noor Azmi Mat Adenan
  • , Kunle Odunsi
  • , Sara H Olson
  • , Irene Orlow
  • , Sandra Orsulic
  • , Rachel Palmieri Weber
  • , James Paul
  • , Celeste Leigh Pearce
  • , Tanja Pejovic
  • , Liisa M Pelttari
  • , Jennifer Permuth-Wey
  • , Malcolm C Pike
  • , Elizabeth M Poole
  • , Susan J Ramus
  • , Harvey A Risch
  • , Barry Rosen
  • , Mary Anne Rossing
  • , Joseph H Rothstein
  • , Anja Rudolph
  • , Ingo B Runnebaum
  • , Iwona K Rzepecka
  • , Helga B Salvesen
  • , Joellen M Schildkraut
  • , Ira Schwaab
  • , Xiao-Ou Shu
  • , Yurii B Shvetsov
  • , Nadeem Siddiqui
  • , Weiva Sieh
  • , Honglin Song
  • , Melissa C Southey
  • , Lara Sucheston
  • , Ingvild L Tangen
  • , Soo-Hwang Teo
  • , Kathryn L Terry
  • , Pamela J Thompson
  • , Shelley S Tworoger
  • , Anne M van Altena
  • , Els Van Nieuwenhuysen
  • , Ignace Vergote
  • , Robert A Vierkant
  • , Shan Wang-Gohrke
  • , Christine Walsh
  • , Nicolas Wentzensen
  • , Alice S Whittemore
  • , Kristine G Wicklund
  • , Lynne R Wilkens
  • , Wlodzimierz Sawicki
  • , Yin-Ling Woo
  • , Xifeng Wu
  • , Anna H Wu
  • , Hannah Yang
  • , Wei Zheng
  • , Argyrios Ziogas
  • , Thomas A Sellers
  • , Matthew L Freedman
  • , Georgia Chenevix-Trench
  • , Paul D P Pharoah
  • , Simon A Gayther
  •  & Andrew Berchuck

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.

Corresponding author

Correspondence to Simon A Gayther.

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Competing interests

The author declare no competing financial interests.

Additional information

A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–9 and Supplementary Note. (PDF 1960 kb)

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The Ovarian Cancer Association Consortium. Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47, 888–897 (2015). https://doi.org/10.1038/ng.3336

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