Meta-Analysis

. 2020 May;52(5):494-504.

doi: 10.1038/s41588-020-0611-8. Epub 2020 Apr 27.

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Maria Teresa Landi¹, D Timothy Bishop², Stuart MacGregor³, Mitchell J Machiela⁴, Alexander J Stratigos^#⁵, Paola Ghiorzo^#^{6

7}, Myriam Brossard⁸, Donato Calista⁹, Jiyeon Choi⁴, Maria Concetta Fargnoli¹⁰, Tongwu Zhang⁴, Monica Rodolfo¹¹, Adam J Trower¹², Chiara Menin¹³, Jacobo Martinez¹⁴, Andreas Hadjisavvas¹⁵, Lei Song⁴, Irene Stefanaki¹⁶, Richard Scolyer^{17

18

19

20}, Rose Yang⁴, Alisa M Goldstein⁴, Miriam Potrony²¹, Katerina P Kypreou¹⁶, Lorenza Pastorino^{6

7}, Paola Queirolo²², Cristina Pellegrini¹⁰, Laura Cattaneo²³, Matthew Zawistowski^{24

25}, Pol Gimenez-Xavier²¹, Arantxa Rodriguez²⁶, Lisa Elefanti¹³, Siranoush Manoukian²⁷, Licia Rivoltini¹¹, Blair H Smith²⁸, Maria A Loizidou¹⁵, Laura Del Regno^{29

30}, Daniela Massi³¹, Mario Mandala³², Kiarash Khosrotehrani^{33

34}, Lars A Akslen^{35

36}, Christopher I Amos³⁷, Per A Andresen³⁸, Marie-Françoise Avril³⁹, Esther Azizi^{40

41}, H Peter Soyer^{34

42}, Veronique Bataille^{43

44}, Bruna Dalmasso^{6

7}, Lisa M Bowdler⁴⁵, Kathryn P Burdon⁴⁶, Wei V Chen⁴⁷, Veryan Codd^{48

49}, Jamie E Craig⁵⁰, Tadeusz Dębniak⁵¹, Mario Falchi^{43

44}, Shenying Fang⁵², Eitan Friedman⁴¹, Sarah Simi³¹, Pilar Galan⁵³, Zaida Garcia-Casado²⁶, Elizabeth M Gillanders⁵⁴, Scott Gordon⁵⁵, Adele Green^{56

57}, Nelleke A Gruis⁵⁸, Johan Hansson⁵⁹, Mark Harland⁶⁰, Jessica Harris⁶¹, Per Helsing⁶², Anjali Henders⁶³, Marko Hočevar⁶⁴, Veronica Höiom⁵⁹, David Hunter^{65

66}, Christian Ingvar⁶⁷, Rajiv Kumar⁶⁸, Julie Lang⁶⁹, G Mark Lathrop⁷⁰, Jeffrey E Lee⁵², Xin Li⁷¹, Jan Lubiński⁷², Rona M Mackie^{69

73}, Maryrose Malt⁵⁶, Josep Malvehy²¹, Kerrie McAloney⁵⁵, Hamida Mohamdi⁸, Anders Molven^{36

74}, Eric K Moses⁷⁵, Rachel E Neale⁷⁶, Srdjan Novaković⁷⁷, Dale R Nyholt^{55

78}, Håkan Olsson^{79

80}, Nicholas Orr⁸¹, Lars G Fritsche⁸², Joan Anton Puig-Butille⁸³, Abrar A Qureshi⁸⁴, Graham L Radford-Smith^{85

86

87}, Juliette Randerson-Moor⁶⁰, Celia Requena²⁶, Casey Rowe³³, Nilesh J Samani^{48

49}, Marianna Sanna^{43

44}, Dirk Schadendorf^{88

89}, Hans-Joachim Schulze⁹⁰, Lisa A Simms⁸⁵, Mark Smithers^{91

92}, Fengju Song⁹³, Anthony J Swerdlow^{94

95}, Nienke van der Stoep⁹⁶, Nicole A Kukutsch⁵⁸, Alessia Visconti^{43

44}, Leanne Wallace⁶³, Sarah V Ward^{97

98}, Lawrie Wheeler⁶¹, Richard A Sturm⁴², Amy Hutchinson^{4

99}, Kristine Jones^{4

99}, Michael Malasky^{4

99}, Aurelie Vogt^{4

99}, Weiyin Zhou^{4

99}, Karen A Pooley¹⁰⁰, David E Elder¹⁰¹, Jiali Han⁷¹, Belynda Hicks^{4

99}, Nicholas K Hayward¹⁰², Peter A Kanetsky¹⁰³, Chad Brummett¹⁰⁴, Grant W Montgomery⁶³, Catherine M Olsen¹⁰⁵, Caroline Hayward¹⁰⁶, Alison M Dunning¹⁰⁷, Nicholas G Martin⁵⁵, Evangelos Evangelou^{108

109}, Graham J Mann^{17

110

111}, Georgina Long^{17

112}, Paul D P Pharoah¹⁰⁷, Douglas F Easton¹⁰⁰, Jennifer H Barrett¹², Anne E Cust^{17

113}, Goncalo Abecasis¹¹⁴, David L Duffy^{42

55}, David C Whiteman¹⁰⁵, Helen Gogas¹¹⁵, Arcangela De Nicolo¹¹⁶, Margaret A Tucker⁴, Julia A Newton-Bishop⁶⁰; GenoMEL Consortium; Q-MEGA and QTWIN Investigators; ATHENS Melanoma Study Group; 23andMe; SDH Study Group; IBD Investigators; Essen-Heidelberg Investigators; AMFS Investigators; MelaNostrum Consortium; Ketty Peris^{29

30}, Stephen J Chanock⁴, Florence Demenais⁸, Kevin M Brown^#⁴, Susana Puig^#²¹, Eduardo Nagore^#²⁶, Jianxin Shi⁴, Mark M Iles¹¹⁷, Matthew H Law¹¹⁸

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. landim@mail.nih.gov.
² Leeds Institute of Medical Research at St James's, Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Dermatology, Andreas Syggros Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Genetics of Rare Cancers, Ospedale Policlinico San Martino, Genoa, Italy.
⁷ Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Genoa, Italy.
⁸ Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-1124, Université Paris Descartes, Paris, France.
⁹ Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
¹⁰ Department of Dermatology & Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
¹¹ Unit of Immunotherapy of Human Tumors, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹² Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
¹³ Immunology and Molecular Oncology Unit, Venito Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁴ Red Valenciana de Biobancos, FISABIO, Valencia, Spain.
¹⁵ Department of EM/Molecular Pathology & The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹⁶ Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.
¹⁷ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹⁹ Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
²⁰ New South Wales Health Pathology, Sydney, New South Wales, Australia.
²¹ Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, CIBERER, Barcelona, Spain.
²² Medical Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
²³ Pathology Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
²⁴ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁵ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁶ Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.
²⁷ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
²⁸ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
²⁹ Institute of Dermatology, Catholic University, Rome, Italy.
³⁰ Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
³¹ Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.
³² Department of Oncology, Giovanni XXIII Hospital, Bergamo, Italy.
³³ UQ Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
³⁴ Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
³⁵ Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
³⁶ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
³⁷ Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
³⁸ Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³⁹ Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.
⁴⁰ Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.
⁴¹ Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁴² Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁴³ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁴⁴ Department of Dermatology, West Herts NHS Trust, Herts, UK.
⁴⁵ Sample Processing, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴⁶ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁴⁷ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴⁸ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
⁴⁹ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵⁰ Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
⁵¹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁵² Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵³ 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, Bobigny, France.
⁵⁴ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
⁵⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁶ Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ CRUK Manchester Institute, Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
⁵⁸ Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands.
⁵⁹ Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
⁶⁰ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁶¹ Translational Research Institute, Institute of Health and Biomedical Innovation, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Queensland, Australia.
⁶² Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁶³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁶⁴ Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁶⁵ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁶ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶⁷ Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.
⁶⁸ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
⁶⁹ Department of Medical Genetics, University of Glasgow, Glasgow, UK.
⁷⁰ McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
⁷¹ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
⁷² International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁷³ Department of Public Health, University of Glasgow, Glasgow, UK.
⁷⁴ Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁷⁵ Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
⁷⁶ Cancer Aetiology & Prevention, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷⁷ Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁷⁸ School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁷⁹ Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund, Sweden.
⁸⁰ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁸¹ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
⁸² Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁸³ Biochemistry and Molecular Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona,CIBERER, Barcelona, Spain.
⁸⁴ Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁸⁵ Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁶ Department of Gastroenterology and Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia.
⁸⁷ University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.
⁸⁸ Department of Dermatology, University Hospital Essen, Essen, Germany.
⁸⁹ German Consortium Translational Cancer Research (DKTK), Heidelberg, Germany.
⁹⁰ Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin, University of Münster, Münster, Germany.
⁹¹ Queensland Melanoma Project, Princess Alexandra Hospital, The University of Queensland, St Lucia, Queensland, Australia.
⁹² Mater Research Institute, The University of Queensland, St Lucia, Queensland, Australia.
⁹³ 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.
⁹⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁹⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁹⁶ Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁷ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
⁹⁸ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹⁹ Cancer Genome Research Laboratory, Leidos Biomedical Research, Bethesda, MD, USA.
¹⁰⁰ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁰¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰² Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁰⁴ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁵ Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰⁶ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁰⁷ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁰⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
¹⁰⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹¹⁰ Centre for Cancer Research, Westmead Institute for Medical Research, Sydney, Australia.
¹¹¹ John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
¹¹² Royal North Shore Hospital, Sydney, Australia.
¹¹³ Cancer Epidemiology and Prevention Research, Sydney School of Public Health, Sydney, Australia.
¹¹⁴ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹¹⁵ First Department of Internal Medicine, Laikon General Hospital Greece, National and Kapodistrian University of Athens, Athens, Greece.
¹¹⁶ Cancer Genomics Program, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹¹⁷ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK. M.M.Iles@leeds.ac.uk.
¹¹⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Matthew.Law@qimrberghofer.edu.au.

^# Contributed equally.

PMID: 32341527
PMCID: PMC7255059
DOI: 10.1038/s41588-020-0611-8

Meta-Analysis

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Maria Teresa Landi et al. Nat Genet. 2020 May.

. 2020 May;52(5):494-504.

doi: 10.1038/s41588-020-0611-8. Epub 2020 Apr 27.

Authors

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. landim@mail.nih.gov.
² Leeds Institute of Medical Research at St James's, Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Dermatology, Andreas Syggros Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
⁶ Genetics of Rare Cancers, Ospedale Policlinico San Martino, Genoa, Italy.
⁷ Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Genoa, Italy.
⁸ Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-1124, Université Paris Descartes, Paris, France.
⁹ Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
¹⁰ Department of Dermatology & Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
¹¹ Unit of Immunotherapy of Human Tumors, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹² Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
¹³ Immunology and Molecular Oncology Unit, Venito Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁴ Red Valenciana de Biobancos, FISABIO, Valencia, Spain.
¹⁵ Department of EM/Molecular Pathology & The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹⁶ Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.
¹⁷ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹⁹ Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
²⁰ New South Wales Health Pathology, Sydney, New South Wales, Australia.
²¹ Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, CIBERER, Barcelona, Spain.
²² Medical Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
²³ Pathology Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
²⁴ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁵ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁶ Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.
²⁷ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
²⁸ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
²⁹ Institute of Dermatology, Catholic University, Rome, Italy.
³⁰ Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
³¹ Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.
³² Department of Oncology, Giovanni XXIII Hospital, Bergamo, Italy.
³³ UQ Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
³⁴ Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
³⁵ Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
³⁶ Department of Pathology, Haukeland University Hospital, Bergen, Norway.
³⁷ Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
³⁸ Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³⁹ Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.
⁴⁰ Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.
⁴¹ Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁴² Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
⁴³ Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
⁴⁴ Department of Dermatology, West Herts NHS Trust, Herts, UK.
⁴⁵ Sample Processing, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁴⁶ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
⁴⁷ Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴⁸ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
⁴⁹ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵⁰ Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
⁵¹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁵² Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵³ 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, Bobigny, France.
⁵⁴ Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
⁵⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁶ Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁵⁷ CRUK Manchester Institute, Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
⁵⁸ Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands.
⁵⁹ Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
⁶⁰ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁶¹ Translational Research Institute, Institute of Health and Biomedical Innovation, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Queensland, Australia.
⁶² Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁶³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁶⁴ Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁶⁵ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁶ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶⁷ Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.
⁶⁸ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
⁶⁹ Department of Medical Genetics, University of Glasgow, Glasgow, UK.
⁷⁰ McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
⁷¹ Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
⁷² International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
⁷³ Department of Public Health, University of Glasgow, Glasgow, UK.
⁷⁴ Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁷⁵ Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
⁷⁶ Cancer Aetiology & Prevention, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁷⁷ Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁷⁸ School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁷⁹ Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund, Sweden.
⁸⁰ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
⁸¹ Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
⁸² Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁸³ Biochemistry and Molecular Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona,CIBERER, Barcelona, Spain.
⁸⁴ Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
⁸⁵ Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁶ Department of Gastroenterology and Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia.
⁸⁷ University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.
⁸⁸ Department of Dermatology, University Hospital Essen, Essen, Germany.
⁸⁹ German Consortium Translational Cancer Research (DKTK), Heidelberg, Germany.
⁹⁰ Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin, University of Münster, Münster, Germany.
⁹¹ Queensland Melanoma Project, Princess Alexandra Hospital, The University of Queensland, St Lucia, Queensland, Australia.
⁹² Mater Research Institute, The University of Queensland, St Lucia, Queensland, Australia.
⁹³ 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.
⁹⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁹⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁹⁶ Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁷ Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
⁹⁸ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹⁹ Cancer Genome Research Laboratory, Leidos Biomedical Research, Bethesda, MD, USA.
¹⁰⁰ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁰¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰² Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁰⁴ Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁵ Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰⁶ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁰⁷ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
¹⁰⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
¹⁰⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹¹⁰ Centre for Cancer Research, Westmead Institute for Medical Research, Sydney, Australia.
¹¹¹ John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
¹¹² Royal North Shore Hospital, Sydney, Australia.
¹¹³ Cancer Epidemiology and Prevention Research, Sydney School of Public Health, Sydney, Australia.
¹¹⁴ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹¹⁵ First Department of Internal Medicine, Laikon General Hospital Greece, National and Kapodistrian University of Athens, Athens, Greece.
¹¹⁶ Cancer Genomics Program, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹¹⁷ Leeds Institute for Data Analytics, University of Leeds, Leeds, UK. M.M.Iles@leeds.ac.uk.
¹¹⁸ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Matthew.Law@qimrberghofer.edu.au.

^# Contributed equally.

PMID: 32341527
PMCID: PMC7255059
DOI: 10.1038/s41588-020-0611-8

Abstract

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10^-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

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Figures

**Extended Data Fig. 1. Quantile-Quantile plot of total CM meta-analysis.**
Quantile-quantile plots of negative log₁₀ two sided P-value derived from a fixed-effects inverse-variance weighted meta-analysis of log(OR) effect-sizes derived from the logistic regression GWAS listed in Supplementary Table 1. All confirmed and self-report cases are included, with a total sample size of 36,760 melanoma cases and 375,188 controls.

**Extended Data Fig. 2. Manhattan plots of melanoma risk loci from total and confirmed-only GWAS-meta-analyses.**
Negative log₁₀ two sided P-value derived from a fixed-effects inverse-variance weighted meta-analysis of log(OR) effect-sizes derived from the logistic regression GWAS (y-axis) are plotted by their chromosome position. The confirmed-only analysis included 30,134 cases with histopathologically confirmed CM, and 81,415 controls. The total CM meta-analysis includes all confirmed and self-report cases, with a total sample size of 36,760 CM cases and 375,188 controls. Multiple-testing corrected genome-wide significance threshold was P<5×10⁻⁸. We display in order the total CM meta-analysis without limiting the y-axis; the pathologically confirmed CM cases only meta-analysis with the y-axis limited to 1×10⁻²⁵ and without a limit to more clearly display loci other than *MC1R.*

**Extended Data Fig. 3. Quantile-Quantile plot of confirmed-only CM meta-analysis.**
Quantile-quantile plots of negative log₁₀ two sided P-value derived from a fixed-effects inverse-variance weighted meta-analysis of log(OR) effect-sizes derived from the logistic regression GWAS listed in Supplementary Table 1. Only cases with histopathologically confirmed CM are included, with a total sample size of 30,134 melanoma cases and 81,415 controls.

**Extended Data Fig. 4. Distribution of pigmentation polygenic risk scores across melanoma histological subtypes.**
The figure shows whether PRS defined based on SNPs associated with hair colour differ across CM histological types (Online Methods; SSM: superficial spreading melanoma; NM: nodular melanoma; LM: lentigo melanoma; Acral: acral lentiginous melanoma). The higher the PRS the lighter the hair colour. When comparing subtype 1 vs. subtype 2, we report the effect size for the linear regression of PRS on subtype 1, including study and principal components as covariates to control for population stratification. The regression coefficient, 95% confidence interval, and statistical significance are shown. The positive beta indicates the PRS is higher in subtype 2 (e.g., non-acral melanomas). This analysis included 9828 SSM, 2137 NM, 900 LM, 353 acral melanoma cases and 44676 controls. Two-sided t-statistic was used for testing significance. P-values reported were not adjusted for multiple comparison.

**Extended Data Fig. 5. LD score regression plots.**
LD score regression was performed for the top 4000 (A) 2000 (B) and 1000 (C) tissue-specific genes from melanocyte and GTEx tissue types (v7 datasets), to assess the enrichment of melanoma heritability in these genomic regions using summary statistics from Total CM GWAS meta-analysis. The level of enrichment and P-values are shown, with an FDR = 0.05 cutoff marked as a dashed horizontal line (See Online Methods for statistical test). Tissue categories are color-coded, and a subset of top individual tissue types are shown on the plot. Tissue types from “Skin” category including melanocytes are highlighted in magenta.

**Extended Data Fig. 6. Effect sizes for confirmed-only meta-analysis versus UKBB self-report set**
For each independent genome-wide significant (P<5×10⁻⁸) lead SNP from the confirmed only meta-analysis (30,134 melanoma cases and 81,415 controls), we plot on the Y-axis UK Biobank self-report GWAS (UKBB SR) log(OR) and standard error from a logistic regression GWAS (1,802 self-report CM cases and 7,208 controls) and on the X-axis we plot the log(OR) and standard error from a fixed-effects inverse-variance weighted meta-analysis of log(OR) effect-sizes derived from the logistic regression GWAS for confirmed melanoma cases listed in Supplementary Table 1. We also report the r² correlation from the linear regression of UKBB SR log(OR) on the confirmed met-analysis estimates, weighted by their standard error.

**Figure 1.. Manhattan plot for the total cutaneous melanoma meta-analysis.**
−log₁₀ of two-sided P-values for SNPs derived from a fixed-effects inverse variance weighted meta-analysis of logistic regression GWAS (Y-axis) plotted against SNP chromosome positions for the total meta-analysis (36,760 melanoma cases and 375,188 controls; for full details of analysis and covariates included see the Online Methods). The y-axis is limited to −log₁₀(1×10⁻²⁵) to truncate strong signals at loci such as *MC1R* and *ASIP*. The full plot is displayed in Extended Data Figure 2. To account for multiple testing, SNPs with a P-value less than 5×10⁻⁸ are deemed significant.

**Figure 2.. Overlap of loci identified by primary and secondary analyses.**
Loci identified in the **total** cutaneous melanoma meta-analysis (CM, green, Supplementary Table 3), the pleiotropic analysis with nevus count (CMnev, blue, Supplementary Table 9) and hair color (CMpig, red, Supplementary Table 10), melanocyte TWAS (TWASmel, yellow, Supplementary Table 10), and TWAS using the expression of three skin tissues (TWAS3skin, orange, Supplementary Table 12).

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References

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Methods References

1. Purcell S et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet 81, 559–575 (2007). - PMC - PubMed
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Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

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Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

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