案例报告：一名患有表皮痣和横纹肌肉瘤的患者中后期HRAS基因突变和带有该突变等位基因的父系11号染色体的增益：证据显示HRAS在肿瘤转化中涉及多重打击机制。
Case Report: Sequential postzygotic HRAS mutation and gains of the paternal chromosome 11 carrying the mutated allele in a patient with epidermal nevus and rhabdomyosarcoma: evidence of a multiple-hit mechanism involving HRAS in oncogenic transformation.
发表日期：2023
作者：
Roberta Zuntini, Chiara Cattani, Lucia Pedace, Evelina Miele, Stefano Giuseppe Caraffi, Stefano Gardini, Elena Ficarelli, Simone Pizzi, Francesca Clementina Radio, Angelica Barone, Simonetta Piana, Patrizia Bertolini, Domenico Corradi, Maria Marinelli, Caterina Longo, Alberico Motolese, Orsetta Zuffardi, Marco Tartaglia, Livia Garavelli
来源：
Frontiers in Genetics
摘要：
我们报道了一个7岁的男孩，患有Blaschko线条型排列的表皮痣（EN），涉及面部、头部、右上肢、胸部和左下肢。他在18个月大时发展出了左侧副睾丸胚胎性横纹肌肉瘤。平行测序鉴定到HRAS基因的一种功能增强变异体（c.37G>C, p.Gly13Arg）同时存在于表皮痣和肿瘤中，但在白细胞或颊黏膜上皮细胞中未发现该变异，表明该变异体属于胚后出现。该变异体在表皮痣和肿瘤DNA样本中分别占总读数的33%和92%，支持肿瘤中的额外体细胞突变。病理学DNA甲基化（DNAm）分析显示肿瘤具有与胚胎性横纹肌肉瘤一致的特征，而基于DNAm数组进行的CNV分析表明，在肿瘤中整个父源11号染色体的拷贝数增加，这个染色体携带了突变的HRAS等位基因，这可能是由于父系同源随后肿瘤中父源染色体的进一步获得。肿瘤中观察到其他结构重排，但未发现其他与RAS-MAPK和PI3K-AKT-MTOR途径相关基因的致病性变异。我们的研究结果进一步证实了“基因剂量效应”对与高活性HRAS功能相关的细胞转化多步骤过程的贡献。版权所有 © 2023 Zuntini, Cattani, Pedace, Miele, Caraffi, Gardini, Ficarelli, Pizzi, Radio, Barone, Piana, Bertolini, Corradi, Marinelli, Longo, Motolese, Zuffardi, Tartaglia and Garavelli.
We report a 7-year-old boy born with epidermal nevi (EN) arranged according to Blaschko's lines involving the face and head, right upper limb, chest, and left lower limb, who developed a left paratesticular embryonal rhabdomyosarcoma at 18 months of age. Parallel sequencing identified a gain-of-function variant (c.37G>C, p.Gly13Arg) of HRAS in both epidermal nevus and tumor but not in leukocytes or buccal mucosal epithelial cells, indicating its postzygotic origin. The variant accounted for 33% and 92% of the total reads in the nevus and tumor DNA specimens, respectively, supporting additional somatic hits in the latter. DNA methylation (DNAm) profiling of the tumor documented a signature consistent with embryonal rhabdomyosarcoma and CNV array analysis inferred from the DNAm arrays and subsequent MLPA analysis demonstrated copy number gains of the entire paternal chromosome 11 carrying the mutated HRAS allele, likely as the result of paternal unidisomy followed by subsequent gain(s) of the paternal chromosome in the tumor. Other structural rearrangements were observed in the tumours, while no additional pathogenic variants affecting genes with role in the RAS-MAPK and PI3K-AKT-MTOR pathways were identified. Our findings provide further evidence of the contribution of "gene dosage" to the multistep process driving cell transformation associated with hyperactive HRAS function.Copyright © 2023 Zuntini, Cattani, Pedace, Miele, Caraffi, Gardini, Ficarelli, Pizzi, Radio, Barone, Piana, Bertolini, Corradi, Marinelli, Longo, Motolese, Zuffardi, Tartaglia and Garavelli.