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

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Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-07-14 , DOI: 10.1038/s41436-021-01240-8
B Dalmasso _{1,

2} , L Pastorino _{1,

2} , V Nathan ₃ , N N Shah ₄ , J M Palmer ₃ , M Howlie ₃ , P A Johansson ₃ , N D Freedman ₄ , B D Carter ₅ , L Beane-Freeman ₄ , B Hicks ₆ , A Molven _{7,

8} , H Helgadottir ₉ , A Sankar ₁₀ , H Tsao ₁₁ , A J Stratigos ₁₂ , P Helsing ₁₃ , R Van Doorn ₁₄ , N A Gruis ₁₄ , M Visser ₁₄ , K A W Wadt ₁₅ , G Mann ₁₆ , E A Holland ₁₆ , E Nagore ₁₇ , M Potrony _{18,

19} , S Puig _{19,

20} , C Menin ₂₁ , K Peris _{22,

23} , M C Fargnoli ₂₄ , D Calista ₂₅ , N Soufir ₂₆ , M Harland ₂₇ , T Bishop ₂₇ , P A Kanetsky ₂₈ , D E Elder ₂₈ , V Andreotti _{1,

2} , I Vanni _{1,

2} , W Bruno _{1,

2} , V Höiom ₉ , M A Tucker ₄ , X R Yang ₄ , P A Andresen ₂₉ , D J Adams ₁₀ , M T Landi ₃₀ , N K Hayward ₃ , A M Goldstein ₄ , P Ghiorzo _{1,

2} , ,

Affiliation

IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, Genoa, Italy.
Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
American Cancer Society, Atlanta, GA, USA.
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Wellman Center for Photomedicine, Department of Dermatology, MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
First Department of Dermatology-Venereology, Andreas Sygros Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Dermatology, Oslo University Hospital, Oslo, Norway.
Department Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, Westmead, Australia.
Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
Biochemistry and Molecular Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Dermatology Department, Melanoma Unit, HospitalClínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Institute of Dermatology, Catholic University of the Sacred Heart, Rome, Italy.
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Dermatology Unit, Maurizio Bufalini Hospital, Cesena, Italy.
Dépatement de Génétique Moléculaire, Hôpital Bichat-Claude Bernard, Paris, France.
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Department of Pathology, Oslo University Hospital, Oslo, Norway.
Divison of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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.

中文翻译：

种系 ATM 变异易患黑色素瘤：GenoMEL 和 MelaNostrum 联盟的联合分析

目的

共济失调毛细血管扩张突变 ( ATM ) 与多种癌症的风险有关，但建立因果关系通常具有挑战性。尽管ATM单核苷酸多态性已与黑色素瘤相关，但已鉴定出很少的功能等位基因。因此， ATM对黑色素瘤易感性的影响尚不清楚。

方法

我们从美国、澳大利亚和欧洲的 22 个地点收集了 2,104 例家族性、多原发性 (MPM) 和散发性黑色素瘤病例，这些病例通过面板、外显子组或基因组测序进行了ATM基因分型，并比较了所选ATM变体的等位基因频率 (AF)该队列与 gnomAD 非芬兰欧洲 (NFE) 数据集之间被分类为功能丧失 (LOF) 和意义不确定的变体 (VUS)。

结果

LOF 变异在我们的研究队列中比在 gnomAD NFE 中更常见，无论是在所有病例（AF = 0.005 和 0.002，OR = 2.6，95% CI = 1.56–4.11， p < 0.01），还是家族 + MPM 病例（AF = 0.0054）和 0.002，OR = 2.97， p < 0.01）。同样，VUS 在所有病例（AF = 0.046 和 0.033，OR = 1.41，95% CI = 1.6–5.09， p < 0.01）和家族 + MPM 病例（AF = 0.053 和 0.033，OR = 1.63， p < 0.01）中均富集。。在提供 1,446 名对照的两个中心的病例对照比较中，LOF 和 VUS 在家族 + MPM 病例中丰富（ p = 0.027， p = 0.018）。