IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, Genoa, Italy.
Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
Genet Med. 2021 Nov;23(11):2087-2095. doi: 10.1038/s41436-021-01240-8. Epub 2021 Jul 14.
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.
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.
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).
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.
共济失调毛细血管扩张突变基因（ATM）与多种癌症的风险相关，但建立因果关系往往具有挑战性。虽然 ATM 单核苷酸多态性与黑色素瘤相关，但很少有功能性等位基因被发现。因此，ATM 对黑色素瘤易感性的影响尚不清楚。
我们从 22 个美国、澳大利亚和欧洲的站点收集了 2104 例家族性、多发性原发性（MPM）和散发性黑色素瘤病例，这些病例通过面板、外显子或基因组测序进行了 ATM 基因分型，并比较了该队列中分类为失功能（LOF）和意义不明的变异体（VUS）的选定 ATM 变体的等位基因频率（AF）与 gnOMAD 非芬兰欧洲人（NFE）数据集之间的差异。
与 gnOMAD NFE 相比，我们的研究队列中 LOF 变体的代表性更高，包括所有病例（AF=0.005 和 0.002，OR=2.6，95%CI=1.56-4.11，p<0.01）和家族性+MPM 病例（AF=0.0054 和 0.002，OR=2.97，p<0.01）。同样，VUS 在所有病例中均呈富集（AF=0.046 和 0.033，OR=1.41，95%CI=1.6-5.09，p<0.01）和家族性+MPM 病例（AF=0.053 和 0.033，OR=1.63，p<0.01）。在两个提供 1446 例对照的中心的病例对照比较中，LOF 和 VUS 在家族性+MPM 病例中富集（p=0.027，p=0.018）。
本研究描述了迄今为止最大的共济失调毛细血管扩张突变基因（ATM）胚系变异黑色素瘤队列研究，支持 ATM 作为黑色素瘤易感性基因的作用，LOF 变异提示中等风险。
