Article | Published:

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Nature Genetics volume 47, pages 987995 (2015) | Download Citation

Abstract

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

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Acknowledgements

Please see the Supplementary Note for acknowledgments.

Author information

Author notes

    • Jeffrey E Lee
    • , Myriam Brossard
    • , Florence Demenais
    •  & Christopher I Amos

    These authors contributed equally to this work.

    • Matthew H Law
    • , D Timothy Bishop
    • , Stuart MacGregor
    •  & Mark M Iles

    These authors jointly supervised this work.

Affiliations

  1. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Matthew H Law
    •  & Stuart MacGregor
  2. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

    • D Timothy Bishop
    • , Jennifer H Barrett
    • , John C Taylor
    • , Mark Harland
    • , Juliette Randerson-Moor
    • , Julia A Newton Bishop
    •  & Mark M Iles
  3. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Jeffrey E Lee
    •  & Shenying Fang
  4. INSERM, UMR 946, Genetic Variation and Human Diseases Unit, Paris, France.

    • Myriam Brossard
    •  & Florence Demenais
  5. Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

    • Myriam Brossard
    •  & Florence Demenais
  6. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Nicholas G Martin
    •  & David L Duffy
  7. Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Western Australia, Australia.

    • Eric K Moses
    •  & Sarah V Ward
  8. Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

    • Fengju Song
  9. Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Rajiv Kumar
  10. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Douglas F Easton
    •  & Karen A Pooley
  11. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Paul D P Pharoah
    •  & Alison M Dunning
  12. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

    • Anthony J Swerdlow
  13. Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.

    • Anthony J Swerdlow
  14. Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.

    • Katerina P Kypreou
    •  & Alexander J Stratigos
  15. Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Lars A Akslen
  16. Department of Pathology, Haukeland University Hospital, Bergen, Norway.

    • Lars A Akslen
    •  & Anders Molven
  17. Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Per A Andresen
  18. Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.

    • Marie-Françoise Avril
  19. Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.

    • Esther Azizi
  20. Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Esther Azizi
    •  & Eitan Friedman
  21. Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.

    • Giovanna Bianchi Scarrà
    •  & Paola Ghiorzo
  22. Laboratory of Genetics of Rare Cancers, Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino l'Istituto Scientifico Tumori Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.

    • Giovanna Bianchi Scarrà
    •  & Paola Ghiorzo
  23. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Kevin M Brown
    • , Alisa M Goldstein
    •  & Maria Teresa Landi
  24. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Tadeusz Dȩbniak
    •  & Jan Lubiński
  25. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • David E Elder
  26. Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Institut National de la Recherche Agronomique (INRA) U1125, Conservatoire National des Arts et Métiers, Communauté d'Université Sorbonne Paris Cité, Bobigny, France.

    • Pilar Galan
  27. Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health, Baltimore, Maryland, USA.

    • Elizabeth M Gillanders
  28. Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.

    • Nelleke A Gruis
    •  & Remco van Doorn
  29. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

    • Johan Hansson
    •  & Veronica Höiom
  30. Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Per Helsing
  31. Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Marko Hočevar
  32. Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.

    • Christian Ingvar
  33. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Peter A Kanetsky
  34. Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Wei V Chen
  35. Department of Medical Genetics, University of Glasgow, Glasgow, UK.

    • Julie Lang
    •  & Rona M Mackie
  36. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.

    • G Mark Lathrop
  37. Department of Public Health, University of Glasgow, Glasgow, UK.

    • Rona M Mackie
  38. Centre for Cancer Research, University of Sydney at Westmead, Millennium Institute for Medical Research and Melanoma Institute Australia, Sydney, New South Wales, Australia.

    • Graham J Mann
  39. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Anders Molven
  40. Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Grant W Montgomery
    •  & Dale R Nyholt
  41. Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Srdjan Novaković
  42. Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund, Sweden.

    • Håkan Olsson
  43. Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.

    • Håkan Olsson
  44. Melanoma Unit, Departments of Dermatology, Biochemistry and Molecular Genetics, Hospital Clinic, Institut d'Investigacions Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  45. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  46. Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

    • Abrar A Qureshi
  47. Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Graham L Radford-Smith
    •  & Lisa A Simms
  48. Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

    • Graham L Radford-Smith
  49. University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.

    • Graham L Radford-Smith
  50. Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Nienke van der Stoep
  51. Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • David C Whiteman
  52. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

    • Jamie E Craig
  53. Department of Dermatology, University Hospital Essen, Essen, Germany.

    • Dirk Schadendorf
  54. German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.

    • Dirk Schadendorf
  55. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

    • Kathryn P Burdon
  56. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Dale R Nyholt
  57. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

    • Nick Orr
  58. Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.

    • Anne E Cust
  59. Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Nicholas K Hayward
  60. Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA.

    • Jiali Han
  61. Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA.

    • Jiali Han
  62. Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin at the University of Münster, Münster, Germany.

    • Hans-Joachim Schulze
  63. Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

    • Christopher I Amos

Consortia

  1. GenoMEL Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  2. Essen-Heidelberg Investigators

    A full list of members and affiliations appears in the Supplementary Note.

  3. The SDH Study Group

    A full list of members and affiliations appears in the Supplementary Note.

  4. Q-MEGA and QTWIN Investigators

    A full list of members and affiliations appears in the Supplementary Note.

  5. AMFS Investigators

    A full list of members and affiliations appears in the Supplementary Note.

  6. ATHENS Melanoma Study Group

    A full list of members and affiliations appears in the Supplementary Note.

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Contributions

M.M.I. and M.H.L. led, designed and carried out the statistical analyses and wrote the manuscript. M. Harland was involved in the Leeds genotyping design. J.C.T. carried out statistical analyses. J.R.-M. and N.v.d.S. carried out genotyping and contributed to the interpretation of genotyping data. J.A.N.B. led the GenoMEL Consortium and contributed to study design. N.A.G. was deputy lead of the consortium and contributed to study design. S.M., N.K.H., D.T.B. and J.H.B. designed and led the overall study. J. Han supervised and carried out statistical analysis of the Harvard GWAS data. F.S. and A.A.Q. carried out statistical analysis of the Harvard GWAS data. C.I.A. led and carried out statistical analysis of the MD Anderson GWAS data. W.V.C., J.E.L. and S.F. contributed to the analysis and interpretation of the MD Anderson GWAS data. F.D. led, designed and contributed to the sample collection, analysis and interpretation of the French MELARISK GWAS and advised on the overall statistical analysis. M.B. contributed to the analysis and interpretation of the French MELARISK GWAS data. M.-F.A. led, designed and contributed to the sample collection of the French MELARISK GWAS. G.M.L. led and contributed to the genotyping and interpretation in the French MELARISK GWAS. R.K. and D.S. led and contributed to the sample collection and analysis for the Heidelberg data set. H.-J.S. contributed to the sample collection and analysis for the Heidelberg data set. S.V.W. led and contributed to the sample collection for the WAMHS study. E.K.M. provided coordination and oversight for the WAMHS study. D.C.W. led, designed and contributed to the sample collection for the SDH data set. J.E.C. led and designed the Glaucoma study. K.P.B. contributed to the analysis and interpretation of the Glaucoma data set. G.L.R.-S. led and contributed to the analysis and interpretation of the IBD data set. L.A.S. contributed to the analysis and interpretation of the IBD data set. G.J.M. led and contributed to the sample collection, analysis and interpretation of the AMFS study. A.E.C. contributed to the sample collection, analysis and interpretation of the AMFS study. D.R.N. contributed to the sample collection and analysis of the Q-MEGA, Endometriosis and QTWIN data sets. N.G.M. led the sample collection and analysis for the Q-MEGA and QTWIN data sets. G.W.M. led the sample collection and analysis for the Endometriosis data sets and contributed to the sample collection and analysis for the Q-MEGA, Endometriosis and QTWIN data sets. D.L.D. contributed to the sample collection and analysis for the Q-MEGA, Endometriosis and QTWIN data sets. K.M.B. contributed to the sample collection and analysis for the Q-MEGA and QTWIN data sets. A.J. Stratigos and K.P.K. interpreted and contributed genotype data for the Athens stage 2 data set. A.M.G., P.A.K. and E.M.G. advised on statistical analysis. D.E.E. contributed to the design of the GenoMEL GWAS. A.J. Swerdlow and N.O. interpreted and contributed genotype data for the Breakthrough Generations Study. L.A.A., P.A.A., E.A., G.B.S., T.D., E.F., P. Ghiorzo, J. Hansson, P.H., M. Hocˇevar, V.H., C.I., M.T.L., J. Lang, R.M.M., A.M., J. Lubin´ski, S.N., H.O., S.P., J.A.P.-B. and R.v.D. contributed to sample collection, analysis and interpretation for the GenoMEL data sets. K.A.P., A.M.D., P.D.P.P. and D.F.E. interpreted and contributed genotype data for the Cambridge stage 2 data set. P. Galan contributed to the collection, analysis and interpretation of the SU.VI.Max French control data set. All authors provided critical review of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Matthew H Law or Mark M Iles.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1–3, 5–8 and 10, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 4

    List of SNPs reaching P < 1 × 10–7.

  2. 2.

    Supplementary Table 9

    SNPs used in bioinformatics annotation.

About this article

Publication history

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Accepted

Published

DOI

https://doi.org/10.1038/ng.3373

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