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

AMFS Investigators; MelaNostrum Consortium; GenoMEL Consortium; Q-MEGA and QTWIN Investigators; ATHENS Melanoma Study Group; 23andMe; The SDH Study Group; IBD Investigators; Essen-Heidelberg Investigators

doi:10.1038/s41588-020-0611-8

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

AMFS Investigators
, MelaNostrum Consortium
, GenoMEL Consortium
, Q-MEGA and QTWIN Investigators
, ATHENS Melanoma Study Group
, 23andMe
, The SDH Study Group
, IBD Investigators
, Essen-Heidelberg Investigators

Clinical Departments

National Institutes of Health
University of Leeds
Queensland Institute of Medical Research
National and Kapodistrian University of Athens
University and San Martino Hospital of Genoa
University of Genoa
Institut national de la santé et de la recherche médicale
Ospedale M. Bufalini
University of L'Aquila
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
IRCCS Istituto Oncologico Veneto - Padova
Red Valenciana de Biobancos
Cyprus Institute of Neurology and Genetics
The University of Sydney
Royal Prince Alfred Hospital
New South Wales Health Pathology
University of Barcelona
Pathology Unit
University of Michigan, Ann Arbor
Instituto Valenciano de Oncologia
University of Dundee
Catholic University of the Sacred Heart
Catholic University of Sacred Heart
University of Florence
Papa Giovanni XXIII Hospital
University of Queensland
Princess Alexandra Hospital
University of Bergen
Dartmouth College
University of Oslo
Université Paris Cité
Sheba Medical Center at Tel Hashomer
King's College London
West Hertfordshire Hospitals NHS Trust
University of Tasmania
University of Texas MD Anderson Cancer Center
University of Leicester
University Hospitals of Leicester NHS Trust
Flinders University
Pomeranian Medical University in Szczecin
University of Paris 13
University of Manchester
Leiden University
Karolinska Institutet
Queensland University of Technology
Institute of Oncology Ljubljana
University of Oxford
Harvard University
Lund University
German Cancer Research Center
University of Glasgow
McGill University
Indiana University-Purdue University Indianapolis
University of Western Australia
Institute of Cancer Research
Brown University
Royal Brisbane and Women's Hospital
University of Duisburg-Essen
German Consortium for Translational Cancer Research (DKTK)
University of Münster
Tianjin Medical University
Memorial Sloan-Kettering Cancer Center
Leidos Inc
University of Cambridge
University of Pennsylvania
Moffitt Cancer Center
University of Edinburgh
University of Ioannina
Imperial College London
Westmead Millennium Institute for Medical Research
Australian National University
Royal North Shore Hospital

Research output: Contribution to journal › Article › peer-review

191 Scopus citations

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.

Original language	English
Pages (from-to)	494-504
Number of pages	11
Journal	Nature Genetics
Volume	52
Issue number	5
DOIs	https://doi.org/10.1038/s41588-020-0611-8
State	Published - 1 May 2020

Funding

Funders	Funder number
Australian Research Council
Melanoma Research Alliance
Cancer Councils New South Wales, Victoria and Queensland
Cancer Council Victoria
Seventh Framework Programme
University of Genoa and Genetics of Rare Cancers
Instituto de Salud Carlos III
Ministry of Health 5×1000 per la Ricerca Corrente to Ospedale Policlinico San Martino
Cerylid Biosciences
AOCS
Cancer Council South Australia
Peter MacCallum Foundation
The Cancer Foundation of Western Australia
National Institutes of Health
de Catalunya
Australian Cancer Research Foundation
Catalan Government, Spain
Division of Cancer Epidemiology and Genetics, National Cancer Institute
Agar family
Cancer Council Tasmania
Cooperative Research Centre for Discovery of Genes for Common Human Diseases
Ovarian Cancer Action
Cancer Council NSW
Cancer Institute NSW
U.S. Department of Health and Human Services
Ospedale Policlinico San Martino
European Regional Development Fund
Ovarian Cancer Australia
Cancer Council Queensland
National Cancer Institute	R01CA133996, R01CA083115, R01CA122838, R01CA049449, R01CA088363, U19CA148112, R01CA100264, P01CA055075, P01CA087969
Horizon 2020 Framework Programme	669026
Medical Research and Materiel Command	DAMD17‐01‐1‐0729
National Health and Medical Research Council	400413, ID400281, 339462, ID400413, 442915, 389891, 241944, 389927
Wellcome Trust	WT084766/Z/08/Z, 084766
European Commission	LSHC-CT-2006-018702
Fundació la Marató de TV3	201331-30
Agència de Gestió d'Ajuts Universitaris i de Recerca	2014_SGR_603
Italian Ministry of the University and Scientific Research	PRIN-2012, 2012JJX494
Cancer Research UK	no.C490/ A16561
Fondo de Investigaciones Sanitarias	PI15/00956, PI15/00716
Associazione Italiana per la Ricerca sul Cancro	IG 15460
Fundación Científica Asociación Española Contra el Cáncer	GCB15152978SOEN
NIH NCI	389892,389938, 552485, CA055075, 443036, 442981, 552498, 496739, 200071, 389875, 380385, APP1049894, 496675, 496610
OCAC	U19CA148112

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41588-020-0611-8

Cite this

AMFS Investigators, MelaNostrum Consortium, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, The SDH Study Group, IBD Investigators, & Essen-Heidelberg Investigators (2020). Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility. Nature Genetics, 52(5), 494-504. https://doi.org/10.1038/s41588-020-0611-8

@article{5a960dc9c42344ea9a75e7c6424f7c93,

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

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 {\texttimes} 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.",

author = "\{AMFS Investigators\} and \{MelaNostrum Consortium\} and \{GenoMEL Consortium\} and \{Q-MEGA and QTWIN Investigators\} and \{ATHENS Melanoma Study Group\} and 23andMe and \{The SDH Study Group\} and \{IBD Investigators\} and \{Essen-Heidelberg Investigators\} and Landi, \{Maria Teresa\} and Bishop, \{D. Timothy\} and Stuart MacGregor and Machiela, \{Mitchell J.\} and Stratigos, \{Alexander J.\} and Paola Ghiorzo and Myriam Brossard and Donato Calista and Jiyeon Choi and Fargnoli, \{Maria Concetta\} and Tongwu Zhang and Monica Rodolfo and Trower, \{Adam J.\} and Chiara Menin and Jacobo Martinez and Andreas Hadjisavvas and Lei Song and Irene Stefanaki and Richard Scolyer and Rose Yang and Goldstein, \{Alisa M.\} and Miriam Potrony and Kypreou, \{Katerina P.\} and Lorenza Pastorino and Paola Queirolo and Cristina Pellegrini and Laura Cattaneo and Matthew Zawistowski and Pol Gimenez-Xavier and Arantxa Rodriguez and Lisa Elefanti and Siranoush Manoukian and Licia Rivoltini and Smith, \{Blair H.\} and Loizidou, \{Maria A.\} and \{Del Regno\}, Laura and Daniela Massi and Mario Mandala and Kiarash Khosrotehrani and Akslen, \{Lars A.\} and Amos, \{Christopher I.\} and Andresen, \{Per A.\} and Avril, \{Marie Fran{\c c}oise\} and Esther Azizi and Soyer, \{H. Peter\} and Veronique Bataille and Bruna Dalmasso and Bowdler, \{Lisa M.\} and Burdon, \{Kathryn P.\} and Eitan Friedman",

note = "Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2020",

month = may,

day = "1",

doi = "10.1038/s41588-020-0611-8",

language = "אנגלית",

volume = "52",

pages = "494--504",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

AMFS Investigators, MelaNostrum Consortium, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe, The SDH Study Group, IBD Investigators & Essen-Heidelberg Investigators 2020, 'Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility', Nature Genetics, vol. 52, no. 5, pp. 494-504. https://doi.org/10.1038/s41588-020-0611-8

TY - JOUR

T1 - Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

AU - AMFS Investigators

AU - MelaNostrum Consortium

AU - GenoMEL Consortium

AU - Q-MEGA and QTWIN Investigators

AU - ATHENS Melanoma Study Group

AU - 23andMe

AU - The SDH Study Group

AU - IBD Investigators

AU - Essen-Heidelberg Investigators

AU - Landi, Maria Teresa

AU - Bishop, D. Timothy

AU - MacGregor, Stuart

AU - Machiela, Mitchell J.

AU - Stratigos, Alexander J.

AU - Ghiorzo, Paola

AU - Brossard, Myriam

AU - Calista, Donato

AU - Choi, Jiyeon

AU - Fargnoli, Maria Concetta

AU - Zhang, Tongwu

AU - Rodolfo, Monica

AU - Trower, Adam J.

AU - Menin, Chiara

AU - Martinez, Jacobo

AU - Hadjisavvas, Andreas

AU - Song, Lei

AU - Stefanaki, Irene

AU - Scolyer, Richard

AU - Yang, Rose

AU - Goldstein, Alisa M.

AU - Potrony, Miriam

AU - Kypreou, Katerina P.

AU - Pastorino, Lorenza

AU - Queirolo, Paola

AU - Pellegrini, Cristina

AU - Cattaneo, Laura

AU - Zawistowski, Matthew

AU - Gimenez-Xavier, Pol

AU - Rodriguez, Arantxa

AU - Elefanti, Lisa

AU - Manoukian, Siranoush

AU - Rivoltini, Licia

AU - Smith, Blair H.

AU - Loizidou, Maria A.

AU - Del Regno, Laura

AU - Massi, Daniela

AU - Mandala, Mario

AU - Khosrotehrani, Kiarash

AU - Akslen, Lars A.

AU - Amos, Christopher I.

AU - Andresen, Per A.

AU - Avril, Marie Françoise

AU - Azizi, Esther

AU - Soyer, H. Peter

AU - Bataille, Veronique

AU - Dalmasso, Bruna

AU - Bowdler, Lisa M.

AU - Burdon, Kathryn P.

AU - Friedman, Eitan

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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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AMFS Investigators, MelaNostrum Consortium, GenoMEL Consortium, Q-MEGA and QTWIN Investigators, ATHENS Melanoma Study Group, 23andMe et al. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility. Nature Genetics. 2020 May 1;52(5):494-504. doi: 10.1038/s41588-020-0611-8

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

Abstract

Funding

UN SDGs

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