POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families
POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families
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DOI：
10.1111/bjd.17443
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发表时间：
2019-07-01
影响因子：
10.3
通讯作者：
Puig, S.
中科院分区：
文献类型：
--
作者：
Potrony, M.;Puig-Butille, J. A.;Puig, S.
背景端粒相关基因的胚系突变，如POT1和TERT，使个体易患家族性黑色素瘤。目的研究西班牙黑色素瘤易感家系(至少2个受累的一级或二级亲属)中POT1和TERT基因种系突变的发生率。方法共纳入228个CDKN2A野生型黑色素瘤易感家系。对每个家系中的1名患者进行POT1筛查，对202个家系中的1名患者进行TERT测序(26个家系因DNA耗尽/降解而被排除在外)。TERT启动子序列被扩展到另外30个CDKN2A突变家系和70名有其他癌症家族史的散发性多原发黑色素瘤(MPM)患者。结果我们鉴定了4个可能致病的POT1胚系突变家系：错义突变c.233T>；C(p.Ile78Thr)；无义突变c.1030G>；T(p.Glu344*)；以及另外两个突变c.255G>；A(r.125_255del)和c.1792G>；A(r.1791_1792insAGTA，p.Asp598Serfs*22)。在1例MPM患者中检测到一个未知意义的TERT启动子突变(c.-125C>；A)，但在家族性黑色素瘤患者中未检测到TERT启动子的胚系突变。结论总体而言，在我们的CDKN2A/CDK4野生型西班牙黑色素瘤易感家系中，1个中心点7%的人携带可能具有破坏性的POT1突变。在我们人群中患有黑色素瘤的家族中，TERT启动子胚系突变的频率极其罕见。
Background Germline mutations in telomere-related genes such as POT1 and TERT predispose individuals to familial melanoma. Objectives To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma-prone families (at least two affected first- or second-degree relatives). Methods Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers. Results We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma. Conclusions Overall, 1 center dot 7% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.