Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia
Dalmasso, Bruna; Pastorino, Lorenza; Nathan, Vaishnavi; Shah, Nirav N.; Palmer, Jane M.; Howlie, Madeleine; Johansson, Peter A.; Freedman, Neal D.; Carter, Brian D.; Beane-Freeman, Laura E.; Hicks, Belynda D.; Molven, Anders; Helgadottir, Hildur; Sankar, Aravind; Tsao, Hensin; Stratigos, Alexander J.; Helsing, Per; van Doorn, Remco; Gruis, Nelleke A.; Visser, Mijke; Wadt, Karin Anna Wallentin; Mann, G.; Holland, Elizabeth A.; Nagore, Eduardo; Potrony, Miriam; Puig, Susana; Menin, Chiara; Peris, Ketty; Fargnoli, Maria Concetta; Calista, Donato; Soufir, Nadem; Harland, Mark; Bishop, Timmi Unger; Kanetsky, Peter A.; Elder, David E.; Andreotti, Virginia; Vanni, Irene; Bruno, William; Höiom, Veronica; Tucker, Margaret Anne; Yang, Xiaohong R.; Andresen, Per Arne; Adams, David James; Landi, Maria Teresa; Hayward, Nicholas K.; Goldstein, Alisa M.; Ghiorzo, Paola
Journal article, Peer reviewed
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Date
2021Metadata
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- Department of Clinical Medicine [2086]
- Registrations from Cristin [10237]
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.