目的:NF1抑癌基因的改变是胚胎性横纹肌肉瘤(ERMS)中第二常见的遗传事件,但它与临床病理特征有关,结果,或者共存的分子事件没有很好的定义。此外,NF1变更,主要在I型神经纤维瘤病(NF1)的背景下,驱动大多数具有发散性RMS分化的恶性周围神经鞘瘤(也称为恶性triton肿瘤[MTT])的发病机制。由于这些实体的病理重叠,区分它们可能具有挑战性。本研究旨在全面分析NF1突变RMS与NF1相关MTT的临床病理和分子谱,以更好地了解其发病机制。
方法:我们调查了22个NF1突变RMS和13个NF1相关MTT对照组的临床病理和分子状况。在匹配的基于肿瘤-正常杂交捕获的靶向DNA下一代测序上测试病例。
结果:在RMS组中,除了一个是ERMS,平均年龄为17岁,而MTT的平均年龄为39岁。3例MTT误诊为ERMS,在一个有临床影响的。ERMS中最常见的共存改变是TP53异常(36%),与NRAS突变互斥(14%)。MTT显示在38%的病例中共存的CDKN2A/B和PRC2复合物改变和H3K27me3表达丧失。NF1突变RMS患者的5年生存率为70%,与MTT相比,5年生存率为33%。所有转移性NF1突变型ERMS均与TP53改变相关。
结论:NF1突变型ERMS缺乏TP53改变的患者可能受益于减量化疗。根据诊断挑战以及重大治疗和预后差异,建议对具有横纹肌母细胞分化的挑战性肿瘤进行分子分析。
OBJECTIVE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis.
METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing.
RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations.
CONCLUSIONS: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.