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

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Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.
Nature Genetics ( IF 30.8 ) Pub Date : 2020-04-27 , DOI: 10.1038/s41588-020-0611-8
Maria Teresa Landi ₁ , D Timothy Bishop ₂ , Stuart MacGregor ₃ , Mitchell J Machiela ₁ , Alexander J Stratigos ₄ , Paola Ghiorzo _{5,

6} , Myriam Brossard ₇ , Donato Calista ₈ , Jiyeon Choi ₁ , Maria Concetta Fargnoli ₉ , Tongwu Zhang ₁ , Monica Rodolfo ₁₀ , Adam J Trower ₁₁ , Chiara Menin ₁₂ , Jacobo Martinez ₁₃ , Andreas Hadjisavvas ₁₄ , Lei Song ₁ , Irene Stefanaki ₁₅ , Richard Scolyer _{16,

17,

18,

19} , Rose Yang ₁ , Alisa M Goldstein ₁ , Miriam Potrony ₂₀ , Katerina P Kypreou ₁₅ , Lorenza Pastorino _{5,

6} , Paola Queirolo ₂₁ , Cristina Pellegrini ₉ , Laura Cattaneo ₂₂ , Matthew Zawistowski _{23,

24} , Pol Gimenez-Xavier ₂₀ , Arantxa Rodriguez ₂₅ , Lisa Elefanti ₁₂ , Siranoush Manoukian ₂₆ , Licia Rivoltini ₁₀ , Blair H Smith ₂₇ , Maria A Loizidou ₁₄ , Laura Del Regno _{28,

29} , Daniela Massi ₃₀ , Mario Mandala ₃₁ , Kiarash Khosrotehrani _{32,

33} , Lars A Akslen _{34,

35} , Christopher I Amos ₃₆ , Per A Andresen ₃₇ , Marie-Françoise Avril ₃₈ , Esther Azizi _{39,

40} , H Peter Soyer _{33,

41} , Veronique Bataille _{42,

43} , Bruna Dalmasso _{5,

6} , Lisa M Bowdler ₄₄ , Kathryn P Burdon ₄₅ , Wei V Chen ₄₆ , Veryan Codd _{47,

48} , Jamie E Craig ₄₉ , Tadeusz Dębniak ₅₀ , Mario Falchi _{42,

43} , Shenying Fang ₅₁ , Eitan Friedman ₄₀ , Sarah Simi ₃₀ , Pilar Galan ₅₂ , Zaida Garcia-Casado ₂₅ , Elizabeth M Gillanders ₅₃ , Scott Gordon ₅₄ , Adele Green _{55,

56} , Nelleke A Gruis ₅₇ , Johan Hansson ₅₈ , Mark Harland ₅₉ , Jessica Harris ₆₀ , Per Helsing ₆₁ , Anjali Henders ₆₂ , Marko Hočevar ₆₃ , Veronica Höiom ₅₈ , David Hunter _{64,

65} , Christian Ingvar ₆₆ , Rajiv Kumar ₆₇ , Julie Lang ₆₈ , G Mark Lathrop ₆₉ , Jeffrey E Lee ₅₁ , Xin Li ₇₀ , Jan Lubiński ₇₁ , Rona M Mackie _{68,

72} , Maryrose Malt ₅₅ , Josep Malvehy ₂₀ , Kerrie McAloney ₅₄ , Hamida Mohamdi ₇ , Anders Molven _{35,

73} , Eric K Moses ₇₄ , Rachel E Neale ₇₅ , Srdjan Novaković ₇₆ , Dale R Nyholt _{54,

77} , Håkan Olsson _{78,

79} , Nicholas Orr ₈₀ , Lars G Fritsche ₈₁ , Joan Anton Puig-Butille ₈₂ , Abrar A Qureshi ₈₃ , Graham L Radford-Smith _{84,

85,

86} , Juliette Randerson-Moor ₅₉ , Celia Requena ₂₅ , Casey Rowe ₃₂ , Nilesh J Samani _{47,

48} , Marianna Sanna _{42,

43} , Dirk Schadendorf _{87,

88} , Hans-Joachim Schulze ₈₉ , Lisa A Simms ₈₄ , Mark Smithers _{90,

91} , Fengju Song ₉₂ , Anthony J Swerdlow _{93,

94} , Nienke van der Stoep ₉₅ , Nicole A Kukutsch ₅₇ , Alessia Visconti _{42,

43} , Leanne Wallace ₆₂ , Sarah V Ward _{96,

97} , Lawrie Wheeler ₆₀ , Richard A Sturm ₄₁ , Amy Hutchinson _{1,

98} , Kristine Jones _{1,

98} , Michael Malasky _{1,

98} , Aurelie Vogt _{1,

98} , Weiyin Zhou _{1,

98} , Karen A Pooley ₉₉ , David E Elder ₁₀₀ , Jiali Han ₇₀ , Belynda Hicks _{1,

98} , Nicholas K Hayward ₁₀₁ , Peter A Kanetsky ₁₀₂ , Chad Brummett ₁₀₃ , Grant W Montgomery ₆₂ , Catherine M Olsen ₁₀₄ , Caroline Hayward ₁₀₅ , Alison M Dunning ₁₀₆ , Nicholas G Martin ₅₄ , Evangelos Evangelou _{107,

108} , Graham J Mann _{16,

109,

110} , Georgina Long _{16,

111} , Paul D P Pharoah ₁₀₆ , Douglas F Easton ₉₉ , Jennifer H Barrett ₁₁ , Anne E Cust _{16,

112} , Goncalo Abecasis ₁₁₃ , David L Duffy _{41,

54} , David C Whiteman ₁₀₄ , Helen Gogas ₁₁₄ , Arcangela De Nicolo ₁₁₅ , Margaret A Tucker ₁ , Julia A Newton-Bishop ₅₉ , , , , , , , , , , Ketty Peris _{28,

29} , Stephen J Chanock ₁ , Florence Demenais ₇ , Kevin M Brown ₁ , Susana Puig ₂₀ , Eduardo Nagore ₂₅ , Jianxin Shi ₁ , Mark M Iles ₁₁ , Matthew H Law ₃

Affiliation

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Leeds Institute of Medical Research at St James's, Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Dermatology, Andreas Syggros Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Genetics of Rare Cancers, Ospedale Policlinico San Martino, Genoa, Italy.
Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Genoa, Italy.
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.
Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
Department of Dermatology & Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Unit of Immunotherapy of Human Tumors, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
Immunology and Molecular Oncology Unit, Venito Institute of Oncology IOV-IRCCS, Padua, Italy.
Red Valenciana de Biobancos, FISABIO, Valencia, Spain.
Department of EM/Molecular Pathology & The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Department of Dermatology, University of Athens School of Medicine, Andreas Sygros Hospital, Athens, Greece.
Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
New South Wales Health Pathology, Sydney, New South Wales, Australia.
Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, CIBERER, Barcelona, Spain.
Medical Oncology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Pathology Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Institute of Dermatology, Catholic University, Rome, Italy.
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.
Department of Oncology, Giovanni XXIII Hospital, Bergamo, Italy.
UQ Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
Department of Pathology, Molecular Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France.
Department of Dermatology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel.
Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dermatology Research Centre, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Department of Dermatology, West Herts NHS Trust, Herts, UK.
Sample Processing, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Cancer and Population Studies, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
CRUK Manchester Institute, Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands.
Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
Translational Research Institute, Institute of Health and Biomedical Innovation, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Queensland, Australia.
Department of Dermatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Department of Surgery, Clinical Sciences, Lund University, Lund, Sweden.
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
Department of Medical Genetics, University of Glasgow, Glasgow, UK.
McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Department of Public Health, University of Glasgow, Glasgow, UK.
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
Cancer Aetiology & Prevention, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
School of Biomedical Sciences and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
Department of Oncology/Pathology, Clinical Sciences, Lund University, Lund, Sweden.
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Biochemistry and Molecular Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona,CIBERER, Barcelona, Spain.
Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Inflammatory Bowel Diseases, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Gastroenterology and Hepatology, Royal Brisbane & Women's Hospital, Brisbane, Queensland, Australia.
University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia.
Department of Dermatology, University Hospital Essen, Essen, Germany.
German Consortium Translational Cancer Research (DKTK), Heidelberg, Germany.
Department of Dermatology, Fachklinik Hornheide, Institute for Tumors of the Skin, University of Münster, Münster, Germany.
Queensland Melanoma Project, Princess Alexandra Hospital, The University of Queensland, St Lucia, Queensland, Australia.
Mater Research Institute, The University of Queensland, St Lucia, Queensland, Australia.
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.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Department of Clinical Genetics, Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cancer Genome Research Laboratory, Leidos Biomedical Research, Bethesda, MD, USA.
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Department of Anesthesiology, University of Michigan, Ann Arbor, MI, USA.
Cancer Control Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
Centre for Cancer Research, Westmead Institute for Medical Research, Sydney, Australia.
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
Royal North Shore Hospital, Sydney, Australia.
Cancer Epidemiology and Prevention Research, Sydney School of Public Health, Sydney, Australia.
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
First Department of Internal Medicine, Laikon General Hospital Greece, National and Kapodistrian University of Athens, Athens, Greece.
Cancer Genomics Program, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

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.

中文翻译：

结合多种风险表型的全基因组关联荟萃分析提供了对皮肤黑色素瘤易感性遗传结构的见解。

大多数对皮肤黑色素瘤的遗传易感性仍有待发现。对 36,760 例黑色素瘤（67% 新基因分型）和 375,188 名对照进行的 Meta 分析全基因组关联研究 (GWAS) 确定了具有 68 个独立单核苷酸多态性的 54 个显着（P < 5 × 10-8）位点。跨地理区域和宿主因素的风险评估分析表明，肢端黑色素瘤亚型与色素沉着完全无关。将这项荟萃分析与痣计数和头发颜色的 GWAS 以及转录组关联方法相结合，发现了总共 85 个皮肤黑色素瘤易感位点的 31 个潜在继发位点。这些发现提供了对皮肤黑色素瘤遗传结构的见解，加强了新生、色素沉着和端粒维持的重要性，

更新日期：2020-04-27

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