Zuntini Roberta, Cattani Chiara, Pedace Lucia, Miele Evelina, Caraffi Stefano Giuseppe, Gardini Stefano, Ficarelli Elena, Pizzi Simone, Radio Francesca Clementina, Barone Angelica, Piana Simonetta, Bertolini Patrizia, Corradi Domenico, Marinelli Maria, Longo Caterina, Motolese Alberico, Zuffardi Orsetta, Tartaglia Marco, Garavelli Livia
Medical Genetics Unit, Azienda USL, IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
Department of Pediatric Hematology, Oncology and Cellular and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Front Genet. 2023 Aug 10;14:1231434. doi: 10.3389/fgene.2023.1231434. eCollection 2023.
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 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 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.
我们报告了一名7岁男孩，出生时即患有沿布拉斯科线分布的表皮痣（EN），累及面部和头部、右上臂、胸部及左下肢，该患儿在18个月大时发生了左侧睾丸旁胚胎性横纹肌肉瘤。平行测序在表皮痣和肿瘤中均鉴定出一个功能获得性变异（c.37G>C，p.Gly13Arg），但在白细胞或口腔黏膜上皮细胞中未检测到，表明其为合子后起源。该变异分别占痣和肿瘤DNA样本总读数的33%和92%，提示肿瘤中存在额外的体细胞突变。肿瘤的DNA甲基化（DNAm）分析显示出与胚胎性横纹肌肉瘤一致的特征，从DNAm阵列推断的CNV阵列分析及随后的MLPA分析表明，携带突变等位基因的整个父源11号染色体存在拷贝数增加，这可能是父源单亲二体随后肿瘤中父源染色体获得额外拷贝的结果。在肿瘤中还观察到其他结构重排，而未发现影响RAS-MAPK和PI3K-AKT-MTOR通路相关基因的其他致病变异。我们的研究结果进一步证明了“基因剂量”在驱动与HRAS功能亢进相关的细胞转化的多步骤过程中的作用。
