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Genome-wide association study identifies three new melanoma susceptibility loci

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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Figure 1: Manhattan plot of results of Cochran-Armitage (CA) trend test stratified by geographic region with −log10 P values shown.
Figure 2: Stratified CA trend tests for the three replicated regions on chromosomes 2, 11 and 21.
Figure 3: Forest plot of the per-allele OR for melanoma for SNPs in the three regions first identified by this study.

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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).

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Authors and Affiliations

Authors

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.

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Correspondence to D Timothy Bishop.

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The authors declare no competing financial interests.

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Barrett, J., Iles, M., Harland, M. et al. Genome-wide association study identifies three new melanoma susceptibility loci. Nat Genet 43, 1108–1113 (2011). https://doi.org/10.1038/ng.959

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