NEK11 as a candidate high-penetrance melanoma susceptibility gene
NEK11 as a candidate high-penetrance melanoma susceptibility gene
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DOI：
10.1136/jmedgenet-2019-106134
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发表时间：
2020-03-01
影响因子：
4
通讯作者：
Gruis, Nelleke
中科院分区：
文献类型：
--
作者：
Christodoulou, Eirini;van Doorn, Remco;Gruis, Nelleke
背景：部分被诊断为皮肤黑色素瘤的患者报告有阳性家族史。CDKN2A和其他几个基因的遗传变异已被证明易患黑色素瘤；然而，在大多数情况下，家族性黑色素瘤的遗传基础仍不清楚。本研究的目的是了解家族性黑色素瘤的遗传基础。方法对一个荷兰黑色素瘤家系进行全外显子测序(WES)分析，寻找新的黑色素瘤易感基因。候选变异的因果关系是通过使用患者来源的组织和数字液滴聚合酶链式反应分析在五个受影响的家庭成员中进行共分离分析来准确量化突变等位基因频率来表征的。结果Wes的应用在NEK11基因(c.1120C>；T，p.Arg374Ter)中发现了一个罕见的无意义变异，在一个荷兰家庭的所有5个受影响成员中都存在共分离。NEK11(NIMA-Related Kinase 11)参与DNA损伤反应，执行G2/M细胞周期检查点。在一个来自变异携带者的黑色素瘤中，这种假定的肿瘤抑制基因的野生型等位基因的体细胞丢失被证明。功能分析表明，NEK11 p.Arg374Ter突变导致蛋白酶体降解导致截短蛋白表达显著降低。结论该家族中发现的NEK11 p.Arg374Ter突变通过蛋白质不稳定导致功能丧失。总的来说，这些发现支持NEK11是黑色素瘤的易感基因。
Background A proportion of patients diagnosed with cutaneous melanoma reports a positive family history. Inherited variants in CDKN2A and several other genes have been shown to predispose to melanoma; however, the genetic basis of familial melanoma remains unknown in most cases. The objective of this study was to provide insight into the genetic basis of familial melanoma.Methods In order to identify novel melanoma susceptibility genes, whole exome sequencing (WES) analysis was applied in a Dutch family with melanoma. The causality of a candidate variant was characterised by performing cosegregation analysis in five affected family members using patient-derived tissues and digital droplet PCR analysis to accurately quantify mutant allele frequency. Functional in-vitro studies were performed to assess the pathogenicity of the candidate variant.Results Application of WES identified a rare, nonsense variant in the NEK11 gene (c.1120C>T, p.Arg374Ter), cosegregating in all five affected members of a Dutch family. NEK11 (NIMA-related Kinase 11) is involved in the DNA damage response, enforcing the G2/M cell cycle checkpoint. In a melanoma from a variant carrier, somatic loss of the wildtype allele of this putative tumour suppressor gene was demonstrated. Functional analyses showed that the NEK11 p.Arg374Ter mutation results in strongly reduced expression of the truncated protein caused by proteasomal degradation.Conclusion The NEK11 p.Arg374Ter variant identified in this family leads to loss-of-function through protein instability. Collectively, these findings support NEK11 as a melanoma susceptibility gene.