Genome-wide association study identifies three new melanoma susceptibility loci

Journal name:
Nature Genetics
Volume:
43,
Pages:
1108–1113
Year published:
DOI:
doi:10.1038/ng.959
Received
Accepted
Published online

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.

At a glance

Figures

  1. Manhattan plot of results of Cochran-Armitage (CA) trend test stratified by geographic region with -log10  P values shown.
    Figure 1: Manhattan plot of results of Cochran-Armitage (CA) trend test stratified by geographic region with −log10  P values shown.

    The solid horizontal line indicates a P value of 10−5. Markers within 50 kb of an SNP associated with melanoma are marked in black for those identified in a previous GWAS and replicated here, and in red for those first identified in the current study. The y axis is truncated at P = 10−15, although three SNPs in the MC1R region have stronger P values up to 2.7 × 10−27, as signified by the box and arrow.

  2. Stratified CA trend tests for the three replicated regions on chromosomes 2, 11 and 21.
    Figure 2: Stratified CA trend tests for the three replicated regions on chromosomes 2, 11 and 21.

    The log10 P values are from the CA trend test (stratified by geographical region) for genotyped and imputed SNPs, as indicated on the left-hand vertical axis. SNPs genotyped for all samples are plotted as circles, SNPs imputed for all samples as crosses and SNPs genotyped for some samples and imputed for others (as a result of chip differences) as squares. The most significant genotyped SNP is colored purple (with its name above), and the degree of LD between that SNP and the others is indicated by color according to the key (red being the greatest degree of LD). The estimated recombination rate is given by the blue line and indicated on the right-hand vertical axis. The genes in the region and their positions are given underneath the graph. Plots were produced using LocusZoom27.

  3. Forest plot of the per-allele OR for melanoma for SNPs in the three regions first identified by this study.
    Figure 3: Forest plot of the per-allele OR for melanoma for SNPs in the three regions first identified by this study.

    Plots show the current evidence for effects by geography and by case type (family history, multiple primaries or early onset) in the genome-wide and replication samples.

References

  1. Cannon-Albright, L.A., Bishop, D.T., Goldgar, C. & Skolnick, M.H. Genetic predisposition to cancer. Important Adv. Oncol. 3955 (1991).
  2. Naldi, L. et al. Cutaneous malignant melanoma in women. Phenotypic characteristics, sun exposure, and hormonal factors: a case-control study from Italy. Ann. Epidemiol. 15, 545550 (2005).
  3. Titus-Ernstoff, L. et al. Pigmentary characteristics and moles in relation to melanoma risk. Int. J. Cancer 116, 144149 (2005).
  4. Holly, E.A., Aston, D.A., Cress, R.D., Ahn, D.K. & Kristiansen, J.J. Cutaneous melanoma in women. I. Exposure to sunlight, ability to tan, and other risk factors related to ultraviolet light. Am. J. Epidemiol. 141, 923933 (1995).
  5. Holly, E.A., Aston, D.A., Cress, R.D., Ahn, D.K. & Kristiansen, J.J. Cutaneous melanoma in women. II. Phenotypic characteristics and other host-related factors. Am. J. Epidemiol. 141, 934942 (1995).
  6. Bataille, V. et al. Risk of cutaneous melanoma in relation to the numbers, types and sites of naevi: a case-control study. Br. J. Cancer 73, 16051611 (1996).
  7. Chang, Y.M. et al. A pooled analysis of melanocytic nevus phenotype and the risk of cutaneous melanoma at different latitudes. Int. J. Cancer 124, 420428 (2009).
  8. Bishop, D.T. et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat. Genet. 41, 920925 (2009).
  9. Raimondi, S. et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int. J. Cancer 122, 27532760 (2008).
  10. Kanetsky, P.A. et al. Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma. Cancer Res. 66, 93309337 (2006).
  11. Gudbjartsson, D.F. et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat. Genet. 40, 886891 (2008).
  12. Falchi, M. et al. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat. Genet. 41, 915919 (2009).
  13. Brown, K.M. et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat. Genet. 40, 838840 (2008).
  14. Duffy, D.L. et al. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am. J. Hum. Genet. 87, 616 (2010).
  15. Duffy, D.L. et al. Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J. Invest. Dermatol. 130, 520528 (2010).
  16. Guedj, M. et al. Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum. Mutat. 29, 11541160 (2008).
  17. Nan, H., Kraft, P., Hunter, D.J. & Han, J. Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in Caucasians. Int. J. Cancer 125, 909917 (2009).
  18. Rafnar, T. et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221227 (2009).
  19. Han, J. et al. A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet. 4, e1000074 (2008).
  20. Fernandez, L.P. et al. SLC45A2: a novel malignant melanoma-associated gene. Hum. Mutat. 29, 11611167 (2008).
  21. Baird, D.M. Variation at the TERT locus and predisposition for cancer. Expert Rev. Mol. Med. 12, e16 (2010).
  22. Yin, M., Yan, J., Wei, S. & Wei, Q. CASP8 polymorphisms contribute to cancer susceptibility: evidence from a meta-analysis of 23 publications with 55 individual studies. Carcinogenesis 31, 850857 (2010).
  23. Lavin, M.F. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat. Rev. Mol. Cell Biol. 9, 759769 (2008).
  24. Garner, C. Upward bias in odds ratio estimates from genome-wide association studies. Genet. Epidemiol. 31, 288295 (2007).
  25. Curtin, J.A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 21352147 (2005).
  26. Newton-Bishop, J.A. et al. Melanocytic nevi, nevus genes, and melanoma risk in a large case-control study in the United Kingdom. Cancer Epidemiol. Biomarkers Prev. 19, 20432054 (2010).
  27. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 23362337 (2010).
  28. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).
  29. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904909 (2006).
  30. Clayton, D. Testing for association on the X chromosome. Biostatistics 9, 593600 (2008).
  31. Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 15391558 (2002).
  32. DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177188 (1986).
  33. Newton-Bishop, J.A. et al. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate. Eur. J. Cancer 47, 732741 (2011).
  34. Newton-Bishop, J.A. et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J. Clin. Oncol. 27, 54395444 (2009).
  35. Gauderman, W.J. & Morrison, J.M. QUANTO 1.1: A Computer Program for Power and Sample Size Calculations for Genetic-Epidemiology Studies. (2006). Available from http://hydra.usc.edu/gxe.

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Author information

  1. These authors contributed equally to this work.

    • Jennifer H Barrett &
    • Mark M Iles

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

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.

A full list of members is provided in the Supplementary Note online.

on behalf of the GenoMEL Consortium

Competing financial interests

The authors declare no competing financial interests.

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