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

Matthew H Law¹, D Timothy Bishop², Jeffrey E Lee^#³, Myriam Brossard^#^{4

5}, Nicholas G Martin⁶, Eric K Moses⁷, Fengju Song⁸, Jennifer H Barrett², Rajiv Kumar⁹, Douglas F Easton¹⁰, Paul D P Pharoah¹¹, Anthony J Swerdlow^{12

13}, Katerina P Kypreou¹⁴, John C Taylor², Mark Harland², Juliette Randerson-Moor², Lars A Akslen^{15

16}, Per A Andresen¹⁷, Marie-Françoise Avril¹⁸, Esther Azizi^{19

20}, Giovanna Bianchi Scarrà^{21

22}, Kevin M Brown²³, Tadeusz Dębniak²⁴, David L Duffy⁶, David E Elder²⁵, Shenying Fang³, Eitan Friedman²⁰, Pilar Galan²⁶, Paola Ghiorzo^{21

22}, Elizabeth M Gillanders²⁷, Alisa M Goldstein²³, Nelleke A Gruis²⁸, Johan Hansson²⁹, Per Helsing³⁰, Marko Hočevar³¹, Veronica Höiom²⁹, Christian Ingvar³², Peter A Kanetsky³³, Wei V Chen³⁴; GenoMEL Consortium; Essen-Heidelberg Investigators; SDH Study Group; Q-MEGA and QTWIN Investigators; AMFS Investigators; ATHENS Melanoma Study Group; Maria Teresa Landi²³, Julie Lang³⁵, G Mark Lathrop³⁶, Jan Lubiński²⁴, Rona M Mackie^{37

35}, Graham J Mann³⁸, Anders Molven^{16

39}, Grant W Montgomery⁴⁰, Srdjan Novaković⁴¹, Håkan Olsson^{42

43}, Susana Puig^{44

45}, Joan Anton Puig-Butille^{44

45}, Abrar A Qureshi⁴⁶, Graham L Radford-Smith^{47

48

49}, Nienke van der Stoep⁵⁰, Remco van Doorn²⁸, David C Whiteman⁵¹, Jamie E Craig⁵², Dirk Schadendorf^{53

54}, Lisa A Simms⁴⁷, Kathryn P Burdon⁵⁵, Dale R Nyholt^{56

40}, Karen A Pooley¹⁰, Nick Orr⁵⁷, Alexander J Stratigos¹⁴, Anne E Cust⁵⁸, Sarah V Ward⁷, Nicholas K Hayward⁵⁹, Jiali Han^{60

61}, Hans-Joachim Schulze⁶², Alison M Dunning¹¹, Julia A Newton Bishop², Florence Demenais^#^{4

5}, Christopher I Amos^#⁶³, Stuart MacGregor¹, Mark M Iles²

Affiliations

¹ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
² Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
³ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-946, Genetic Variation and Human Diseases Unit, Paris, France.
⁵ Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
⁶ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁷ Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Western Australia, Australia.
⁸ Departments 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, P. R. China.
⁹ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg Germany.
¹⁰ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹³ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁴ Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.
¹⁵ Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹⁶ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹⁸ Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.
¹⁹ Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.
²⁰ Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²¹ Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
²² Laboratory of Genetics of Rare Cancers, Istituto di ricovero e cura a carattere scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
²⁴ International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
²⁵ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁶ Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Institut National de la Santé et de la Recherche Médicale (INSERM U1153), Institut National de la Recherche Agronomique (INRA U1125), Conservatoire National des Arts et Métiers, Communauté d'Université Sorbonne Paris Cité, F-93017 Bobigny, France.
²⁷ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.
²⁸ Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
²⁹ Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³¹ Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
³² Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.
³³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³⁴ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³⁵ Department of Medical Genetics, University of Glasgow, Glasgow, UK.
³⁶ McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
³⁷ Department of Public Health, University of Glasgow, Glasgow UK.
³⁸ Centre for Cancer Research, University of Sydney at Westmead, Millennium Institute for Medical Research and Melanoma Institute Australia, Sydney, Australia.
³⁹ Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴⁰ Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴¹ Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁴² Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund; Sweden.
⁴³ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁴⁴ Melanoma Unit, Dermatology Department & Biochemistry and Molecular Genetics Departments, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.
⁴⁵ Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
⁴⁶ Department of Dermatology, The Warren Alpert Medical School of Brown University, Rhode Island, USA.
⁴⁷ Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴⁸ Department of Gastroenterology and Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Australia.
⁴⁹ University of Queensland School of Medicine, Herston Campus, Brisbane, Australia.
⁵⁰ Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵¹ Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁵² Department of Ophthalmology, Flinders University, Adelaide, Australia.
⁵³ Department of Dermatology, University Hospital Essen, Essen, Germany.
⁵⁴ German Consortium Translational Cancer Research (DKTK), Heidelberg, Germany.
⁵⁵ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁵⁶ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵⁷ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
⁵⁸ Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Australia.
⁵⁹ Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶⁰ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA.
⁶¹ Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA.
⁶² Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin at the University of Münster, Münster, Germany.
⁶³ Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

^# Contributed equally.

PMID: 26237428
PMCID: PMC4557485
DOI: 10.1038/ng.3373

Meta-Analysis

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

Matthew H Law et al. Nat Genet. 2015 Sep.

. 2015 Sep;47(9):987-995.

doi: 10.1038/ng.3373. Epub 2015 Aug 3.

Authors

Affiliations

¹ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
² Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
³ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-946, Genetic Variation and Human Diseases Unit, Paris, France.
⁵ Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
⁶ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁷ Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Western Australia, Australia.
⁸ Departments 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, P. R. China.
⁹ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg Germany.
¹⁰ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹³ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁴ Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.
¹⁵ Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹⁶ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
¹⁷ Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹⁸ Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.
¹⁹ Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.
²⁰ Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²¹ Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
²² Laboratory of Genetics of Rare Cancers, Istituto di ricovero e cura a carattere scientifico Azienda Ospedaliera Universitaria (IRCCS AOU) San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
²⁴ International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
²⁵ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²⁶ Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Institut National de la Santé et de la Recherche Médicale (INSERM U1153), Institut National de la Recherche Agronomique (INRA U1125), Conservatoire National des Arts et Métiers, Communauté d'Université Sorbonne Paris Cité, F-93017 Bobigny, France.
²⁷ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.
²⁸ Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.
²⁹ Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³¹ Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
³² Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.
³³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³⁴ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³⁵ Department of Medical Genetics, University of Glasgow, Glasgow, UK.
³⁶ McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
³⁷ Department of Public Health, University of Glasgow, Glasgow UK.
³⁸ Centre for Cancer Research, University of Sydney at Westmead, Millennium Institute for Medical Research and Melanoma Institute Australia, Sydney, Australia.
³⁹ Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴⁰ Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴¹ Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁴² Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund; Sweden.
⁴³ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁴⁴ Melanoma Unit, Dermatology Department & Biochemistry and Molecular Genetics Departments, Hospital Clinic, Institut de Investigacó Biomèdica August Pi Suñe, Universitat de Barcelona, Barcelona, Spain.
⁴⁵ Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
⁴⁶ Department of Dermatology, The Warren Alpert Medical School of Brown University, Rhode Island, USA.
⁴⁷ Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴⁸ Department of Gastroenterology and Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Australia.
⁴⁹ University of Queensland School of Medicine, Herston Campus, Brisbane, Australia.
⁵⁰ Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵¹ Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁵² Department of Ophthalmology, Flinders University, Adelaide, Australia.
⁵³ Department of Dermatology, University Hospital Essen, Essen, Germany.
⁵⁴ German Consortium Translational Cancer Research (DKTK), Heidelberg, Germany.
⁵⁵ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁵⁶ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵⁷ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
⁵⁸ Cancer Epidemiology and Services Research, Sydney School of Public Health, The University of Sydney, Australia.
⁵⁹ Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶⁰ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana, USA.
⁶¹ Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, USA.
⁶² Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin at the University of Münster, Münster, Germany.
⁶³ Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.

^# Contributed equally.

PMID: 26237428
PMCID: PMC4557485
DOI: 10.1038/ng.3373

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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Figures

**Figure 1. Manhattan plot of the Stage one meta-analysis of GWAS of CMM from Europe, the USA and Australia**
The *P_fixed* Stage one value for all SNPs present in at least two studies have been plotted using a log₁₀(–log₁₀) transform to truncate the strong signals at *MC1R* (P < 10^–92) on chromosome 16 and *CDKN2A* (P < 10^–31) on chromosome 9. The total Stage one meta-analysis included 11 CMM GWAS, totaling 12,874 cases and 23,203 controls. P < 5 × 10^–8 (genome-wide significance) and P < 1 × 10^–6 are indicated by a red and a blue line respectively. 18 loci reached genome-wide significance in Stage one. The 2 newly-confirmed loci 11q13.3 (*CCND1*) and 15q13.1 (*HERC2*/*OCA2*) are indicated by * and the 5 novel loci 2p22.2, 6p22.3, 7p21.1, 9q31.2 and 10q24.33 are highlighted by **. 2p22.2 (*RMDN2*/*CYP1B1*) and 10q24.33 (*OBFC1*) were genome-wide significant only in the Overall meta-analysis (Supplementary Table 3).

**Figure 2. Regional association plots for novel genome-wide significant loci 2p22.2, 6p22.3, 7p21.1, 9q31.2, 10q24.33 and the newly-confirmed region, 15q13.1 (*OCA2*)**
The negative log₁₀ of *P_fixed* values for SNPs from the Stage one meta-analysis of 12,874 cases and 23,203 controls have been plotted against their genomic position (Mb) using LocusZoom. The rs ID is listed for the peak SNP in each region (purple diamond). The P-values and effect sizes for listed SNPs can be found in Supplementary Table 3. For the remaining SNPs the color indicates linkage disequilibrium r² with the peak SNP. Neither rs2995264 in 10q24.33 nor rs6750047 in 2p22.2 are genome-wide significant in Stage one, but reach this in the Overall meta-analysis. The plot for 11q13.3 (*CCND1*) can be found in Supplementary Figure 4.

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References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical