Letter | Published:

Genome-wide association study identifies three new melanoma susceptibility loci

Nature Genetics volume 43, pages 11081113 (2011) | Download Citation

Abstract

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

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Acknowledgements

The authors are extremely grateful for the contributions of D. Seminara to the work of GenoMEL and also for the support of G. Cross (University of Leeds) for maintaining the study wiki. Overall, the GenoMEL Consortium is indebted to the organizational skills of P. Affleck.

This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from their website (see URLs). Funding for the project was provided by the Wellcome Trust under award 076113.

The authors thank the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) cooperative group for giving access to data of the EGEA study. We acknowledge that the biological specimens of the French Familial Melanoma Study Group were obtained from the Institut Gustave Roussy and Fondation Jean Dausset–CEPH Biobanks.

The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project grant (C8216/A6129) and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. Funding specific to particular locations is acknowledged below.

Australia: Melanoma Research Alliance, US NCI (CA088363, CA083115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council of Australia (NHMRC) (107359, 200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 402761, 443036, 442915, 442981, 496610, 496675, 520018, 496739, 552485 and 552498), the Cancer Councils NSW, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre (CRC) for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne) and the Australian Cancer Research Foundation.

Cambridge: D.F.E. is a Principal Research Fellow of Cancer Research UK. SEARCH is funded by grants from Cancer Research UK (C8197/A10123, C8197/A10123 and C490/A10124). A.M.D. has been supported by a Cancer Research UK grant (C8197/A10865) and by the Joseph Mitchell Fund.

Emilia-Romagna: US NCI grant to M.T. Landi (CA5558).

Genoa: IRCSS 2007 Italian Ministry of Health (DGRST4/4235-P1.9.A.B.) and Fondazione CARIGE, PRIN 2008 to G. Bianchi-Scarrà.

Houston: NIH grants to the M.D. Anderson Cancer Center (CA100264 and CA33996).

Leeds: Cancer Research UK Programme grants for Genetic epidemiology of cancer (C588/A10589 and C588/A4994) and Cancer Research UK Project grant (C8216/A6129) and Leeds Cancer Research UK Centre (C37059/A11941).

Leiden: Grant provided by European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)–Netherlands hub (CO18).

Lund: Funding by the Swedish Cancer Society, Swedish Research Council, Region Skåne funds, Kamprad Foundation.

Norway: Grants from the Comprehensive Cancer Center, Oslo University Hospital (SE0728) and the Norwegian Cancer Society (71512-PR-2006-0356).

Paris: Grants from Institut National du Cancer (INCa-PL016) and Ligue Nationale Contre Le Cancer (PRE05/FD and PRE 09/FD) to F. Demenais, Programme Hospitalier de Recherche Clinique (AOM-07-195) to M.-F. Avril and F. Demenais, Institut National du Cancer (Melanoma Network RS 13), Association pour la Recherche sur le Cancer (ARC A09/5/5003) and Société Française de Dermatologie (SFD2009) to B.B.-deP. B.B.-deP. has been awarded an INSERM Research Fellowship for hospital-based scientists.

Stockholm: Grants were provided by the Swedish Cancer Society (100279), the Swedish Research Council (K2006-74X-20141-01-3), Radiumhemmet Research Funds (101152) and Karolinska Institutet Research Funds (2010Fobi0450).

Utah: NIH award to L.A. Cannon-Albright (CA102422).

Author information

Author notes

    • Jennifer H Barrett
    •  & Mark M Iles

    These authors contributed equally to this work.

Affiliations

  1. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James's University Hospital, Leeds, UK.

    • Jennifer H Barrett
    • , Mark M Iles
    • , Mark Harland
    • , John C Taylor
    • , Juliette Randerson-Moor
    • , Helen Snowden
    • , Julia A Newton Bishop
    •  & D Timothy Bishop
  2. Viertel Centre for Research in Cancer Control, The Cancer Council, Queensland, Spring Hill, Brisbane, Queensland, Australia.

    • Joanne F Aitken
  3. Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Per Arne Andresen
  4. The Gade Institute, University of Bergen, Bergen, Norway.

    • Lars A Akslen
    •  & Anders Molven
  5. Deptartment of Pathology, Haukeland University Hospital, Bergen, Norway.

    • Lars A Akslen
    •  & Anders Molven
  6. Westmead Millennium Institute, Westmead, New South Wales, Australia.

    • Bruce K Armstrong
    • , Richard F Kefford
    •  & Graham J Mann
  7. Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Descartes, Paris, France.

    • Marie-Francoise Avril
  8. Department of Dermatology and the Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Esther Azizi
    •  & Eitan Friedman
  9. Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

    • Bert Bakker
    •  & Nienke van der Stoep
  10. Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Wilma Bergman
    • , Frans A van Nieuwpoort
    •  & Nelleke A Gruis
  11. Department of Internal Medicine, University of Genoa, Genoa, Italy.

    • Giovanna Bianchi-Scarrà
    • , Paola Ghiorzo
    •  & Lorenza Pastorino
  12. INSERM, U946, Fondation Jean-Dausset–CEPH, Paris, France.

    • Brigitte Bressac-de Paillerets
    • , Eve Corda
    •  & Florence Demenais
  13. Département de Biopathologie, Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France.

    • Brigitte Bressac-de Paillerets
  14. Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy.

    • Donato Calista
    •  & Giorgio Landi
  15. Division of Genetic Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Lisa A Cannon-Albright
  16. Fondation Jean Dausset–CEPH, Paris, France.

    • Eve Corda
    • , G Mark Lathrop
    •  & Florence Demenais
  17. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Victoria, Australia.

    • Anne E Cust
    • , Graham G Giles
    • , John L Hopper
    •  & Mark A Jenkins
  18. Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

    • Anne E Cust
  19. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Tadeusz Dębniak
    •  & Jan Lubiński
  20. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • David Duffy
    • , Nicholas G Martin
    • , Grant W Montgomery
    • , David C Whiteman
    • , Stuart MacGregor
    •  & Nicholas K Hayward
  21. Department of Oncology, University of Cambridge, Cambridge, UK.

    • Alison M Dunning
    •  & Douglas F Easton
  22. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Douglas F Easton
  23. Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Eitan Friedman
  24. UMR U557 Inserm; U1125 Institut national de la Recherche Agronomique, Conservatoire national des arts et métiers, Centre de Recherche en Nutrition Humaine, Ile de France, Bobigny, France.

    • Pilar Galan
  25. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Graham G Giles
  26. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

    • Johan Hansson
    • , Veronica Höiom
    •  & Rainer Tuominen
  27. Institute of Oncology Ljubljana, Ljubljana, Slovenia.

    • Marko Hocevar
    •  & Srdjan Novakovic
  28. Department of Surgery, University Hospital Lund, Lund, Sweden.

    • Christian Ingvar
  29. ServiceXS, Leiden, The Netherlands.

    • Bart Janssen
  30. Department of Oncology, University Hospital Lund, Lund, Sweden.

    • Göran Jönsson
    •  & Håkan Olsson
  31. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Maria Teresa Landi
    •  & Alisa M Goldstein
  32. Department of Medical Genetics, University of Glasgow, Glasgow, UK.

    • Julie Lang
    •  & Rona Mackie
  33. Public Health and Health Policy, University of Glasgow, Glasgow, UK.

    • Rona Mackie
  34. Melanoma Unit, Dermatology Department, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.

    • Josep Malvehy
    • , Susana Puig
    •  & Joan Anton Puig-Butille
  35. Centre of Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.

    • Susana Puig
    •  & Joan Anton Puig-Butille
  36. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Patricia Van Belle
    •  & David E Elder
  37. Commissariat à l′Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France.

    • Diana Zelenika
    •  & G Mark Lathrop
  38. Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jiali Han
  39. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jiali Han
  40. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Jiali Han
  41. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Shenying Fang
  42. Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Jeffrey E Lee
  43. Department of Epidemiology Unit 1365, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Qingyi Wei
  44. Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.

    • Elizabeth M Gillanders
  45. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland, USA.

    • Kevin M Brown
  46. Centre for Clinical Epidemiology & Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  47. Department of Biostatistics & Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
  48. Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Christopher I Amos
  49. Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie, Paris, France.

    • Florence Demenais

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Contributions

J.H.B. and M.M.I. led and carried out the statistical analysis, contributed to the design of the study and were members of the writing team. M. Harland contributed to the design of the study and provided genotyping information. J.C.T. carried out statistical analyses and was a member of the writing team. J.F.A., P.A.A., L.A.A., B.K.A., M.-F.A., E.A., W.B., D.C., A.E.C., D.D., A.M.D., D.F.E., E.F., P. Ghiorzo, G.G.G., M. Hocevar, V.H., C.I., M.A.J., G.J., G.L., M.T.L., J. Lang, R.M., J.M., N.G.M., A.M., G.W.M., S.N., L.P., J.A.P.-B., R.T., N.v.d.S., J. Hansson and D.C.W. contributed to the identification of suitable samples for the study. B.B. contributed to the design of the study and supervised the initial processing of samples. G.B.-S., K.M.B., B.B.-deP., L.A.C.-A., T.D., D.E.E., J. Hansson, J.L.H., R.F.K., J. Lubiński, F.A.v.N., H.O., S.P. and P.V.B. contributed to the design of the study. H.S. and B.J. carried out genotyping and contributed to the interpretation of genotyping data. P. Galan, J.R.-M. and D.Z. contributed to the interpretation of genotyping data. J. Han contributed results of a confirmatory study. C.I.A., S.F., J.E.L. and Q.W. led and contributed analyses from the Houston study. N.K.H., G.J.M. and S.M. led and contributed results from the Australian study. G.M.L. provided genotyping information and contributed to the interpretation of genotype data. F.D., P.A.K., E.C., A.M.G. and E.M.G. advised on statistical analysis and contributed to the design of the study. N.A.G. was consortium deputy lead and contributed to the design of the study. J.A.N.B. was overall consortium lead and contributed to the design of the study. D.T.B. led the analysis group, contributed to the design of the study and was a member of the writing team.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to D Timothy Bishop.

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DOI

https://doi.org/10.1038/ng.959

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