Saoud Carla, Gundem Gunes, Domenico Dylan, Arango-Ossa Juan E, Reed Damon, Vaynrub Max, Papaemmanouil Elli, Bale Tejus A, Linos Konstantinos
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Genes Chromosomes Cancer. 2025 Jan;64(1):e70025. doi: 10.1002/gcc.70025.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, presenting with heterogeneous clinical and molecular subtypes. While gene fusions are predominantly associated with alveolar RMS, spindle cell RMS, especially congenital and intraosseous variants, are also linked to specific gene fusions. Furthermore, recently, FGFR1 kinase-driven RMSs were published. Here, we describe a case of RMS harboring an EWSR1::NF2 gene fusion, a deletion-driven genetic alteration that has not been previously documented in RMS or other soft tissue tumors. The patient was a 29-year-old female who presented with a lobulated ankle mass. Histologic examination revealed a malignant round cell tumor extensively infiltrating large nerve bundles. Immunohistochemical analysis demonstrated rhabdomyoblastic differentiation, consistent with rhabdomyosarcoma. While some areas showed features resembling the sclerosing and others the embryonal subtypes, the overall findings were considered unclassifiable. Targeted RNA sequencing revealed EWSR1(exon 9):: NF2(exon 7) gene fusion, which was confirmed on whole genome and targeted DNA sequencing. The latter did not yield specific diagnostic insights but revealed mutations in TSC2 (p.T1330M), ZFHX3 (p.A301T), and a NOTCH3 rearrangement, all of unknown oncogenic significance. MYC gene amplification was detected, but there was no evidence of chromosome 8 amplification or chromosome 11p15 loss of heterozygosity. Whole genome sequencing revealed a low tumor mutation burden (2.69/Mb) and showed no other significant potentially oncogenic events. DNA methylation studies using dimensionality reduction and unsupervised clustering placed the case within the embryonal RMS subtype. Although the absence of other oncogenic driver alterations suggests that the fusion may have played a pivotal role in pathogenesis, we cannot exclude the possibility that it represents a passenger alteration rather than a true driver mutation. If the former is true, further studies will be required to determine whether this fusion represents a novel RMS subtype or a rare driver in existing subtypes of RMS.
横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤，具有异质性的临床和分子亚型。虽然基因融合主要与肺泡型RMS相关，但梭形细胞RMS，尤其是先天性和骨内型变体，也与特定的基因融合有关。此外，最近有关于FGFR1激酶驱动的RMS的报道。在此，我们描述了一例携带EWSR1::NF2基因融合的RMS病例，这种由缺失驱动的基因改变在RMS或其他软组织肿瘤中尚未见报道。患者为一名29岁女性，表现为分叶状踝关节肿块。组织学检查显示为恶性圆形细胞瘤，广泛浸润大神经束。免疫组化分析显示有横纹肌母细胞分化，符合横纹肌肉瘤。虽然有些区域表现出类似硬化型的特征，另一些区域表现出胚胎型的特征，但总体结果被认为无法分类。靶向RNA测序显示EWSR1（外显子9）::NF2（外显子7）基因融合，全基因组和靶向DNA测序证实了这一点。后者未产生具体的诊断性见解，但揭示了TSC2（p.T1330M）、ZFHX3（p.A301T）的突变以及NOTCH3重排，所有这些的致癌意义均未知。检测到MYC基因扩增，但没有证据表明存在8号染色体扩增或11号染色体p15杂合性缺失。全基因组测序显示肿瘤突变负荷较低（2.69/Mb），且未发现其他显著的潜在致癌事件。使用降维和无监督聚类的DNA甲基化研究将该病例归为胚胎型RMS亚型。虽然缺乏其他致癌驱动改变表明该融合可能在发病机制中起关键作用，但我们不能排除它代表一个过客改变而非真正驱动突变的可能性。如果前者属实，则需要进一步研究以确定这种融合是否代表一种新的RMS亚型或现有RMS亚型中的罕见驱动因素。
