PURPOSE Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS). EXPERIMENTAL DESIGN Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive. The 10 most common genetic alterations were associated with locoregional control (LC), disease-free survival (DFS), and overall survival (OS). Tumor mutational burden (TMB), defined as the total number of somatic nonsynonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes. RESULTS Median age at diagnosis was 16.4 years and median follow-up, 2.1 years. Patients with fusion-negative RMS had more genomic alterations and a higher TMB than those with fusion-positive RMS (mean number of genomic alterations, 6.0 vs. 2.9; P = 0.007 and mean TMB, 2.6 vs. 1.0; P = 0.01). Genetic alterations in TP53 were associated with worse OS (P = 0.03). High TMB (defined as the top quartile ≥ 2.8) was associated with worse LC (P = 0.05), DFS (P = 0.04), and OS (P = 0.01), with significance retained on multivariable analysis after controlling for risk group, fusion status, and receipt of chemotherapy as per pediatric protocols. CONCLUSIONS High TMB was associated with worse clinical outcomes in patients with RMS. With further validation, TMB and other genomic classifiers may be combined with traditional clinicopathologic risk factors to guide risk stratification and ultimately treatment decisions.

中文翻译：

---

横纹肌肉瘤临床结果的基因组决定因素。

目的 下一代测序的可用性增加已允许对各种儿科肿瘤进行基因组表征，尽管对治疗反应的基因组决定因素在很大程度上仍是未知的。我们试图评估横纹肌肉瘤 (RMS) 临床结果的基因组景观和基因组决定因素。实验设计 29,067 名在我们机构使用具有完整记录的 468 基因 oncopanel 进行基因组分析的患者中，87 名患有 RMS，其中 22 名融合阳性。10 种最常见的基因改变与局部控制 (LC)、无病生存 (DFS) 和总生存 (OS) 相关。肿瘤突变负荷 (TMB)，定义为标准化为已测序兆碱基数量的体细胞非同义突变的总数，也与临床结果相关。结果 诊断时的中位年龄为 16.4 岁，中位随访时间为 2.1 年。与融合阳性 RMS 患者相比，融合阴性 RMS 患者具有更多的基因组改变和更高的 TMB（基因组改变的平均数，6.0 对 2.9；P = 0.007；平均 TMB，2.6 对 1.0；P = 0.01）。TP53 的遗传改变与较差的 OS 相关（P = 0.03）。高 TMB（定义为最高四分位数 ≥ 2.8）与较差的 LC（P = 0.05）、DFS（P = 0.04）和 OS（P = 0.01）相关，在控制风险组、融合后的多变量分析中仍保持显着性状态，并根据儿科方案接受化疗。结论 高 TMB 与 RMS 患者较差的临床结果相关。经进一步验证，