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Mutation analysis of multiple pilomatricomas in a patient with myotonic dystrophy type 1 suggests a DM1-associated hypermutation phenotype.

1 例my性肌营养不良 1 型患者多发性毛母质瘤的突变分析提示DM1-associated的超突变表型。

  • 影响因子:3.02
  • DOI:10.1371/journal.pone.0230003
  • 作者列表:"Rübben A","Wahl RU","Eggermann T","Dahl E","Ortiz-Brüchle N","Cacchi C
  • 发表时间:2020-03-10
Abstract

:Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease which results from an expansion of repetitive DNA elements within the 3' untranslated region of the DMPK gene. Some patients develop multiple pilomatricomas as well as malignant tumors in other tissues. Mutations of the catenin-β gene (CTNNB1) could be demonstrated in most non-syndromic pilomatricomas. In order to gain insight into the molecular mechanisms which might be responsible for the occurrence of multiple pilomatricomas and cancers in patients with DM1, we have sequenced the CTNNB1 gene of four pilomatricomas and of one pilomatrical carcinoma which developed in one patient with molecularly proven DM1 within 4 years. We further analyzed the pilomatrical tumors for microsatellite instability as well as by NGS for mutations in 161 cancer-associated genes. Somatic and independent point-mutations were detected at typical hotspot regions of CTNNB1 (S33C, S33F, G34V, T41I) while one mutation within CTNNB1 represented a duplication mutation (G34dup.). Pilomatricoma samples were analyzed for microsatellite instability and expression of mismatch repair proteins but no mutated microsatellites could be detected and expression of mismatch repair proteins MLH1, MSH2, MSH6, PMS2 was not perturbed. NGS analysis only revealed one heterozygous germline mutation c.8494C>T; p.(Arg2832Cys) within the ataxia telangiectasia mutated gene (ATM) which remained heterozygous in the pilomatrical tumors. The detection of different somatic mutations in different pilomatricomas and in the pilomatrical carcinoma as well as the observation that the patient developed multiple pilomatricomas and one pilomatrical carcinoma over a short time period strongly suggest that the patient displays a hypermutation phenotype. This hypermutability seems to be tissue and gene restricted. Simultaneous transcription of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might constitute an explanation for the observed tissue and gene specificity of hypermutability observed in DM1 patients. Elucidation of putative mechanisms responsible for hypermutability in DM1 patients requires further research.

摘要

: My性肌营养不良 1 型 (DM1) 是一种遗传性神经肌肉疾病,是DMPK基因 3 '非翻译区重复DNA元件扩增的结果。一些患者发展为多发性毛母质瘤以及其他组织中的恶性肿瘤。在大多数非综合征性毛母质瘤中可以证明连环蛋白-β 基因 (CTNNB1) 的突变。为了深入了解可能导致DM1 患者多发毛母质瘤和癌症发生的分子机制,我们对 4 例毛母质瘤和 1 例毛母质癌的CTNNB1 基因进行了测序,该肿瘤在 4 年内发生在 1 例分子证实为DM1 的患者中。我们进一步分析了毛母质肿瘤的微卫星不稳定性以及 161 个癌症相关基因突变的NGS。在CTNNB1 的典型热点区域 (S33C、S33F、G34V、T41I) 检测到体细胞和独立的点突变,而CTNNB1 内的一个突变代表重复突变 (G34dup.)。分析毛母质瘤样本的微卫星不稳定性和错配修复蛋白的表达,但未检测到突变的微卫星,错配修复蛋白MLH1 、MSH2 、MSH6 、PMS2 的表达不受干扰。NGS分析仅发现共济失调毛细血管扩张症突变基因 (ATM) 内有一个杂合种系突变c.8494C>T; p.(Arg2832Cys),该基因在毛母质肿瘤中保持杂合。在不同的毛母质瘤和毛母质癌中检测到不同的体细胞突变,以及观察到患者在短时间内发生了多个毛母质瘤和一个毛母质癌,这强烈表明患者表现出超突变表型。这种超突变似乎是组织和基因受限的。在循环毛囊中同时转录突变的DMPK基因和CTNNB1 基因可能构成了在DM1 患者中观察到的超突变的组织和基因特异性的解释。DM1 患者过度突变的假定机制需要进一步研究。

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皮肤肿瘤方向

皮肤肿瘤是发生在皮肤的细胞增生性疾病,是一种常见病。发生于皮内或皮下组织的新生物,种类很多,临床上分良性肿瘤和恶性肿瘤。恶性肿瘤可以不断增殖,引起转移,威胁生命,称为皮肤癌。

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