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

Maria Teresa Landi; D Timothy Bishop; Stuart MacGregor; Mitchell J Machiela; Alexander J Stratigos; Paola Ghiorzo; Myriam Brossard; Donato Calista; Jiyeon Choi; Maria Concetta Fargnoli; Tongwu Zhang; Monica Rodolfo; Adam J Trower; Chiara Menin; Jacobo Martinez; Andreas Hadjisavvas; Lei Song; Irene Stefanaki; Richard Scolyer; Rose Yang; Alisa M Goldstein; Miriam Potrony; Katerina P Kypreou; Lorenza Pastorino; Paola Queirolo; Cristina Pellegrini; Laura Cattaneo; Matthew Zawistowski; Pol Gimenez-Xavier; Arantxa Rodriguez; Lisa Elefanti; Siranoush Manoukian; Licia Rivoltini; Blair H Smith; Maria A Loizidou; Laura Del Regno; Daniela Massi; Mario Mandala; Kiarash Khosrotehrani; Lars A Akslen; Christopher I Amos; Per A Andresen; Marie-Françoise Avril; Esther Azizi; H Peter Soyer; Veronique Bataille; Wei V Chen; David Hunter; Nicholas Orr; Kevin M Brown; GenoMEL Consortium

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

Maria Teresa Landi, D Timothy Bishop, Stuart MacGregor, Mitchell J Machiela, Alexander J Stratigos, Paola Ghiorzo, Myriam Brossard, Donato Calista, Jiyeon Choi, Maria Concetta Fargnoli, Tongwu Zhang, Monica Rodolfo, Adam J Trower, Chiara Menin, Jacobo Martinez, Andreas Hadjisavvas, Lei Song, Irene Stefanaki, Richard Scolyer, Rose YangAlisa M Goldstein, Miriam Potrony, Katerina P Kypreou, Lorenza Pastorino, Paola Queirolo, Cristina Pellegrini, Laura Cattaneo, Matthew Zawistowski, Pol Gimenez-Xavier, Arantxa Rodriguez, Lisa Elefanti, Siranoush Manoukian, Licia Rivoltini, Blair H Smith, Maria A Loizidou, Laura Del Regno, Daniela Massi, Mario Mandala, Kiarash Khosrotehrani, Lars A Akslen, Christopher I Amos, Per A Andresen, Marie-Françoise Avril, Esther Azizi, H Peter Soyer, Veronique Bataille, Wei V Chen, David Hunter, Nicholas Orr, Kevin M Brown, GenoMEL Consortium

School of Medicine, Dentistry and Biomedical Sciences

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

141 Citations (Scopus)

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
Early online date	27 Apr 2020
DOIs	https://doi.org/10.1038/s41588-020-0611-8
Publication status	Published - 01 May 2020

Keywords

Female
Genetic Loci/genetics
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study/methods
Genotype
Humans
Male
Melanoma/genetics
Phenotype
Pigmentation/genetics
Polymorphism, Single Nucleotide/genetics
Skin Neoplasms/genetics

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Landi, M. T., Bishop, D. T., MacGregor, S., Machiela, M. J., Stratigos, A. J., Ghiorzo, P., Brossard, M., Calista, D., Choi, J., Fargnoli, M. C., Zhang, T., Rodolfo, M., Trower, A. J., Menin, C., Martinez, J., Hadjisavvas, A., Song, L., Stefanaki, I., Scolyer, R., ... GenoMEL Consortium (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{2170cc771bf34ffe93a3bb8c1512c322,

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 × 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.",

keywords = "Female, Genetic Loci/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genotype, Humans, Male, Melanoma/genetics, Phenotype, Pigmentation/genetics, Polymorphism, Single Nucleotide/genetics, Skin Neoplasms/genetics",

author = "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 Marie-Fran{\c c}oise Avril and Esther Azizi and Soyer, {H Peter} and Veronique Bataille and Chen, {Wei V} and David Hunter and Nicholas Orr and Brown, {Kevin M} and {GenoMEL Consortium}",

year = "2020",

month = may,

day = "1",

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

language = "English",

volume = "52",

pages = "494--504",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

Landi, MT, Bishop, DT, MacGregor, S, Machiela, MJ, Stratigos, AJ, Ghiorzo, P, Brossard, M, Calista, D, Choi, J, Fargnoli, MC, Zhang, T, Rodolfo, M, Trower, AJ, Menin, C, Martinez, J, Hadjisavvas, A, Song, L, Stefanaki, I, Scolyer, R, Yang, R, Goldstein, AM, Potrony, M, Kypreou, KP, Pastorino, L, Queirolo, P, Pellegrini, C, Cattaneo, L, Zawistowski, M, Gimenez-Xavier, P, Rodriguez, A, Elefanti, L, Manoukian, S, Rivoltini, L, Smith, BH, Loizidou, MA, Del Regno, L, Massi, D, Mandala, M, Khosrotehrani, K, Akslen, LA, Amos, CI, Andresen, PA, Avril, M-F, Azizi, E, Soyer, HP, Bataille, V, Chen, WV, Hunter, D, Orr, N, Brown, KM & GenoMEL Consortium 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 - 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 - Chen, Wei V

AU - Hunter, David

AU - Orr, Nicholas

AU - Brown, Kevin M

AU - GenoMEL Consortium

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.

KW - Female

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Genotype

KW - Humans

KW - Male

KW - Melanoma/genetics

KW - Phenotype

KW - Pigmentation/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Skin Neoplasms/genetics

U2 - 10.1038/s41588-020-0611-8

DO - 10.1038/s41588-020-0611-8

M3 - Article

C2 - 32341527

SN - 1061-4036

VL - 52

SP - 494

EP - 504

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

Abstract

Keywords

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