Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.
Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.
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DOI：
10.1136/jmg-2022-108776
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发表时间：
2023-07
影响因子：
4
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中科院分区：
文献类型：
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端粒1基因（POT 1）保护中的致病性种系变异与一系列肿瘤类型的易感性相关，包括黑色素瘤、神经胶质瘤、白血病和心脏血管肉瘤。我们对2928例欧洲血统黑色素瘤病例和3298例对照的POT 1基因的所有编码外显子进行了测序，确定了43种蛋白质改变的遗传变异。我们对所有错义和停止获得的变体进行了POT 1-端粒结合测定，发现了9种损害或破坏蛋白质-端粒复合物形成的变体，并且我们通过分子动力学模拟进一步定义了变体在调节端粒长度和复合物形成中的作用。我们确定POT 1编码变异是一般人群中黑色素瘤负担的次要因素，只有约0.5%的黑色素瘤病例在该基因中携带生殖系致病变异，但应在具有黑色素瘤和/或多种恶性肿瘤家族史的个体中进行筛查。
Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein–telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.
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