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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

: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.


: 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。



作者列表:["Zhang B","Li L","Zhang N","Zhao M","Liu Y","Wei L","Ma L","Xu Z"]

METHODS::Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0-1.5 mg/m2 /day with a target drug level of 5-10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.

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作者列表:["Pham CT","Juhasz M","Sung CT","Mesinkovska NA"]

METHODS:BACKGROUND:Human papillomavirus (HPV) infections are associated with common dermatologic and nondermatologic diseases. Although HPV vaccines are well established as preventive measures for genital warts and cervical neoplasia, their use as therapeutic agents deserves greater attention. OBJECTIVE:To evaluate the use of HPV vaccine(s) as a treatment modality for cutaneous and/or mucosal disease. METHODS:A primary literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in January 2019 by using the PubMed and Cochrane databases. RESULTS:A total of 63 articles with 4439 patients were included. The majority of patients with cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas were successfully treated with HPV vaccination. Preliminary data on patients with pre-existing anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia is promising. LIMITATIONS:This review was limited by the lack of controls, patients' previous HPV vaccination status, and publication bias. CONCLUSION:The commercially available three-dose, quadrivalent HPV vaccine is a potential therapeutic option for the treatment of cutaneous warts, recurrent respiratory papillomatosis, and squamous and basal cell carcinomas. Noncommercially available HPV vaccines demonstrate therapeutic response for treating anogenital warts, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulvar intraepithelial neoplasia. The vaccine's efficacy as an adjunct therapy for HPV-associated cutaneous and/or mucosal disease warrants further exploration.

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作者列表:["Lang UE","Love NR","Cheung C","McCalmont TH","Kim J"]

METHODS::Our understanding of melanoma precursors and progression to melanoma has developed as a result of advances in the field of molecular diagnostics. We now better understand the potential for genetic heterogeneity within a single lesion. Combined tumors can pose a diagnostic challenge when deciding the line between benign and malignant, which in turn has direct implications for patient management. Primary cilia (PC) are ubiquitous sensory organelles that have essential functions in cellular proliferation, differentiation, and development. The ciliation index (percentage of ciliated melanocytes) has been shown to reliably differentiate melanoma, which fail to ciliate, from melanocytic nevi, which retain PC. We therefore analyzed the potential for using the ciliation index to differentiate benign and malignant components in combined melanocytic lesions. We collected patient samples (n = 10) of unequivocal combined lesions with both melanoma and associated nevus components. Melanocytes were highlighted with SOX10 and costained with gamma-Tubulin and acetylated alpha-Tubulin to highlight the basal body and cilium, respectively. The number of melanocytes retaining cilia under high-power microscopy was examined. The melanoma component had average of 4% ciliation (SD: 7%), whereas the associated nevus component was significantly higher with 59% ciliation (SD: 17%). These data show that PC may be a reliable means of distinguishing benign from malignant components within a single tumor. The ciliation index may be a helpful tool in distinguishing challenging cases of combined lesions of melanoma in situ with a dermal nevus component from invasive melanoma, thus promoting improved staging and clinical management.

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