Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

B. Dalmasso; L. Pastorino; V. Nathan; N. N. Shah; J. M. Palmer; M. Howlie; P. A. Johansson; N. D. Freedman; B. D. Carter; L. Beane-Freeman; B. Hicks; A. Molven; H. Helgadottir; A. Sankar; H. Tsao; A. J. Stratigos; P. Helsing; R. Van Doorn; N. A. Gruis; M. Visser; K. A.W. Wadt; G. Mann; E. A. Holland; E. Nagore; M. Potrony; S. Puig; C. Menin; Ketty Peris; M. C. Fargnoli; Maria Concetta Fargnoli; D. Calista; N. Soufir; M. Harland; T. Bishop; P. A. Kanetsky; D. E. Elder; V. Andreotti; I. Vanni; W. Bruno; V. Höiom; M. A. Tucker; X. R. Yang; P. A. Andresen; D. J. Adams; M. T. Landi; N. K. Hayward; A. M. Goldstein; P. Ghiorzo

doi:10.1038/s41436-021-01240-8

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

B. Dalmasso
, L. Pastorino
, V. Nathan
, N. N. Shah
, J. M. Palmer
, M. Howlie
, P. A. Johansson
, N. D. Freedman
, B. D. Carter
, L. Beane-Freeman
, B. Hicks
, A. Molven
, H. Helgadottir
, A. Sankar
, H. Tsao
, A. J. Stratigos
, P. Helsing
, R. Van Doorn
, N. A. Gruis
, M. Visser

K. A.W. Wadt, G. Mann, E. A. Holland, E. Nagore, M. Potrony, S. Puig, C. Menin, Ketty Peris, M. C. Fargnoli, Maria Concetta Fargnoli, D. Calista, N. Soufir, M. Harland, T. Bishop, P. A. Kanetsky, D. E. Elder, V. Andreotti, I. Vanni, W. Bruno, V. Höiom, M. A. Tucker, X. R. Yang, P. A. Andresen, D. J. Adams, M. T. Landi, N. K. Hayward, A. M. Goldstein, P. Ghiorzo

San Martino Hospital Genoa
Queensland Institute of Medical Research
National Institutes of Health
American Cancer Society
Leidos Inc
University of Bergen
Karolinska Institutet
Wellcome Sanger Institute
Harvard University
National and Kapodistrian University of Athens
University of Oslo
Leiden University
University of Copenhagen
The University of Sydney
Instituto Valenciano de Oncologia
University of Barcelona
Centro de Investigación Biomédica en Red
IRCCS Istituto Oncologico Veneto - Padova
University of L'Aquila
Ospedale M. Bufalini
Université Paris Cité
University of Leeds
University of South Florida

Research output: Contribution to journal › Article

Abstract

Purpose: Ataxia–Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Original language	English
Pages (from-to)	2087-2095
Number of pages	9
Journal	Genetics in Medicine
Volume	23
DOIs	https://doi.org/10.1038/s41436-021-01240-8
Publication status	Published - 2021

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Ataxia Telangiectasia
Ataxia Telangiectasia Mutated Proteins
Australia
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Melanoma

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10.1038/s41436-021-01240-8

Cite this

Dalmasso, B., Pastorino, L., Nathan, V., Shah, N. N., Palmer, J. M., Howlie, M., Johansson, P. A., Freedman, N. D., Carter, B. D., Beane-Freeman, L., Hicks, B., Molven, A., Helgadottir, H., Sankar, A., Tsao, H., Stratigos, A. J., Helsing, P., Van Doorn, R., Gruis, N. A., ... Ghiorzo, P. (2021). Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia. Genetics in Medicine, 23, 2087-2095. https://doi.org/10.1038/s41436-021-01240-8

@article{82f4c7c303af4633bfa3b5b764202388,

title = "Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia",

abstract = "Purpose: Ataxia{\textendash}Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95\% CI = 1.56{\textendash}4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95\% CI = 1.6{\textendash}5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case{\textendash}control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.",

keywords = "Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Australia, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Melanoma, Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Australia, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Melanoma",

author = "B. Dalmasso and L. Pastorino and V. Nathan and Shah, \{N. N.\} and Palmer, \{J. M.\} and M. Howlie and Johansson, \{P. A.\} and Freedman, \{N. D.\} and Carter, \{B. D.\} and L. Beane-Freeman and B. Hicks and A. Molven and H. Helgadottir and A. Sankar and H. Tsao and Stratigos, \{A. J.\} and P. Helsing and \{Van Doorn\}, R. and Gruis, \{N. A.\} and M. Visser and Wadt, \{K. A.W.\} and G. Mann and Holland, \{E. A.\} and E. Nagore and M. Potrony and S. Puig and C. Menin and Ketty Peris and Fargnoli, \{M. C.\} and Fargnoli, \{Maria Concetta\} and D. Calista and N. Soufir and M. Harland and T. Bishop and Kanetsky, \{P. A.\} and Elder, \{D. E.\} and V. Andreotti and I. Vanni and W. Bruno and V. H{\"o}iom and Tucker, \{M. A.\} and Yang, \{X. R.\} and Andresen, \{P. A.\} and Adams, \{D. J.\} and Landi, \{M. T.\} and Hayward, \{N. K.\} and Goldstein, \{A. M.\} and P. Ghiorzo",

year = "2021",

doi = "10.1038/s41436-021-01240-8",

language = "English",

volume = "23",

pages = "2087--2095",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

}

Dalmasso, B, Pastorino, L, Nathan, V, Shah, NN, Palmer, JM, Howlie, M, Johansson, PA, Freedman, ND, Carter, BD, Beane-Freeman, L, Hicks, B, Molven, A, Helgadottir, H, Sankar, A, Tsao, H, Stratigos, AJ, Helsing, P, Van Doorn, R, Gruis, NA, Visser, M, Wadt, KAW, Mann, G, Holland, EA, Nagore, E, Potrony, M, Puig, S, Menin, C, Peris, K, Fargnoli, MC, Fargnoli, MC, Calista, D, Soufir, N, Harland, M, Bishop, T, Kanetsky, PA, Elder, DE, Andreotti, V, Vanni, I, Bruno, W, Höiom, V, Tucker, MA, Yang, XR, Andresen, PA, Adams, DJ, Landi, MT, Hayward, NK, Goldstein, AM & Ghiorzo, P 2021, 'Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia', Genetics in Medicine, vol. 23, pp. 2087-2095. https://doi.org/10.1038/s41436-021-01240-8

TY - JOUR

T1 - Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

AU - Dalmasso, B.

AU - Pastorino, L.

AU - Nathan, V.

AU - Shah, N. N.

AU - Palmer, J. M.

AU - Howlie, M.

AU - Johansson, P. A.

AU - Freedman, N. D.

AU - Carter, B. D.

AU - Beane-Freeman, L.

AU - Hicks, B.

AU - Molven, A.

AU - Helgadottir, H.

AU - Sankar, A.

AU - Tsao, H.

AU - Stratigos, A. J.

AU - Helsing, P.

AU - Van Doorn, R.

AU - Gruis, N. A.

AU - Visser, M.

AU - Wadt, K. A.W.

AU - Mann, G.

AU - Holland, E. A.

AU - Nagore, E.

AU - Potrony, M.

AU - Puig, S.

AU - Menin, C.

AU - Peris, Ketty

AU - Fargnoli, M. C.

AU - Fargnoli, Maria Concetta

AU - Calista, D.

AU - Soufir, N.

AU - Harland, M.

AU - Bishop, T.

AU - Kanetsky, P. A.

AU - Elder, D. E.

AU - Andreotti, V.

AU - Vanni, I.

AU - Bruno, W.

AU - Höiom, V.

AU - Tucker, M. A.

AU - Yang, X. R.

AU - Andresen, P. A.

AU - Adams, D. J.

AU - Landi, M. T.

AU - Hayward, N. K.

AU - Goldstein, A. M.

AU - Ghiorzo, P.

PY - 2021

Y1 - 2021

N2 - Purpose: Ataxia–Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

AB - Purpose: Ataxia–Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. Methods: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. Results: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). Conclusion: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

KW - Ataxia Telangiectasia

KW - Ataxia Telangiectasia Mutated Proteins

KW - Australia

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Humans

KW - Melanoma

KW - Ataxia Telangiectasia

KW - Ataxia Telangiectasia Mutated Proteins

KW - Australia

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Humans

KW - Melanoma

UR - http://hdl.handle.net/10807/197955

U2 - 10.1038/s41436-021-01240-8

DO - 10.1038/s41436-021-01240-8

M3 - Article

SN - 1098-3600

VL - 23

SP - 2087

EP - 2095

JO - Genetics in Medicine

JF - Genetics in Medicine

ER -

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

Abstract

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Keywords

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