Abstract：
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.
摘要：
多形性横纹肌肉瘤（PRMS）是一种罕见且高度侵袭性的肉瘤，主要发生在中年人的深层软组织中，并显示出不同程度的骨骼肌分化。由于病理特征与胚胎性横纹肌肉瘤（ERMS）重叠，因此诊断具有挑战性。Triton恶性肿瘤,和其他多形性肉瘤。由于迄今为止尚未描述PRMS背后的复发性遗传改变，辅助分子诊断测试在亚分类中没有用.在这里，我们对14个PRMS的特征明确的队列进行基因组分析，使用经临床验证的DNA靶向下一代测序（NGS）面板（MSK-IMPACT），与23例ERMS和其他多形性肉瘤（未分化多形性肉瘤和多形性脂肪肉瘤）的对照组进行比较。PRMS队列包括8名男性和6名女性，年龄中位数为53岁（范围31-76岁）。尽管类似的肿瘤突变负担，PRMS的基因组景观，TP53（79％）和RB1（43％）改变的频率很高，与ERMS形成鲜明对比，4%和0%，分别。CDKN2A缺失在PRMS中更为常见（43%），与ERMS（13%）相比。相比之下,ERMS在RAS途径中具有体细胞驱动突变，在BCOR中具有功能缺失突变，这在PRMS中是不存在的。PRMS中的拷贝数变异显示了多个染色体臂水平的变化，最常见的是chr17p和chr22q的收益和chr6q的损失。值得注意的是,在ERMS中常见的chr8增益(61%)在PRMS中明显不存在。其他多形性肉瘤的基因组谱总体上类似于PRMS，显示TP53、RB1和CDKN2A的共有改变。PRMS的总生存期和无进展生存期明显低于ERMS（p<0.0005）。我们的发现表明，PRMS的分子景观与其他成年多形性肉瘤一致，并且与ERMS不同。因此，NGS测定可以应用于选择具有挑战性的情况下进行精细分类。最后,我们的数据证实了PRMS包含在多形性肉瘤的治疗支架中，鉴于它们的临床结局具有可比性。
