| Title: |
Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia. |
| Authors: |
Dalmasso, B; 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; 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; GenoMEL; MelaNostrum consortia |
| Source: |
Genetics in medicine : official journal of the American College of Medical Genetics; vol 23, iss 11, 2087-2095; 1098-3600 |
| Publisher Information: |
eScholarship, University of California 2021-11-01 |
| Document Type: |
Electronic Resource |
| Abstract: |
PurposeAtaxia-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.MethodsFrom 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.ResultsLOF 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).ConclusionThis 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. |
| Index Terms: |
GenoMEL; MelaNostrum consortia; Humans; Melanoma; Ataxia Telangiectasia; Genetic Predisposition to Disease; Germ-Line Mutation; Australia; Ataxia Telangiectasia Mutated Proteins; Cancer; Human Genome; Genetics; Aetiology; 2.1 Biological and endogenous factors; Clinical Sciences; Genetics & Heredity; article |
| URL: |
https://escholarship.org/uc/item/62b5x2jx; https://escholarship.org/ |
| Availability: |
Open access content. Open access content; public |
| Note: |
application/pdf; Genetics in medicine : official journal of the American College of Medical Genetics vol 23, iss 11, 2087-2095 1098-3600 |
| Other Numbers: |
CDLER oai:escholarship.org:ark:/13030/qt62b5x2jx; qt62b5x2jx; https://escholarship.org/uc/item/62b5x2jx; https://escholarship.org/; 1344354527 |
| Contributing Source: |
UC MASS DIGITIZATION; From OAIster®, provided by the OCLC Cooperative. |
| Accession Number: |
edsoai.on1344354527 |
| Database: |
OAIster |