Institute of Pathology, Department of General Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Soft-Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mod Pathol. 2021 Aug;34(8):1558-1569. doi: 10.1038/s41379-021-00804-y. Epub 2021 Apr 12.
Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS.
子宫胚胎性横纹肌肉瘤 (ERMS) 最近被证实经常存在 DICER1 突变。有趣的是，迄今为止，仅报道了极少数发生在子宫外的与 DICER1 相关的 ERMS，主要位于泌尿生殖道。我们的目标是研究一组泌尿生殖道肿瘤中 DICER1 突变 (DICER1-mut) 和 DICER1 野生型 (DICER1-wt) ERMS 的临床病理和分子特征。我们收集了一组 17 例 ERMS，包括 9 例子宫（4 例子宫体和 5 例子宫颈）、1 例阴道和 7 例泌尿道肿瘤。DNA 测序显示，9/9 例子宫 ERMS 存在 DICER1 突变。我们队列中的所有其他 ERMS 均为 DICER1-wt。DICER1-mut 和 DICER1-wt ERMS 患者的诊断中位年龄分别为 36 岁和 5 岁。有限的随访数据（可用于 15/17 例患者）表明，DICER1-mut ERMS 的临床病程可能比 DICER1-wt ERMS 更具侵袭性。仅在 DICER1-mut ERMS 中观察到的组织学特征是软骨结节（9/9 例 DICER1-mut ERMS），其中 1 例伴有骨化灶。在 DICER1-mut 和 DICER1-wt ERMS 中均发现的复发性突变影响 KRAS、NRAS 和 TP53。拷贝数分析显示，在不依赖 DICER1 突变状态的情况下，存在 2、3 和 8 号染色体的常见增益，具有相似的结构变异。对我们研究队列的基于阵列的全基因组 DNA 甲基化数据进行无监督层次聚类，以及包括泌尿生殖道和非泌尿生殖道位置的不同 RMS 亚型的扩展甲基化数据集（n=102），揭示了 DICER1-mut ERMS 的一个独特聚类。这种肿瘤与 DICER1-wt ERMS、肺泡 RMS 和 MYOD1 突变梭形细胞和硬化 RMS 的聚类明显不同。只有 1 例先前诊断为发生在 6 岁男孩上颌的 ERMS 肿瘤与子宫的 DICER1-mut ERMS 聚类。随后的测序分析在后者中发现了两个 DICER1 突变。我们的结果表明，DICER1-mut ERMS 可能有资格成为 RMS 未来分类中的一个独特亚型。
