Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma.
Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma.
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DOI：
10.1158/1078-0432.ccr-19-2631
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发表时间：
2020-03-01
期刊：
影响因子：
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通讯作者：
Wolden SL
中科院分区：
文献类型：
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作者：
Casey DL;Wexler LH;Pitter KL;Samstein RM;Slotkin EK;Wolden SL
下一代测序的增加使得各种儿科肿瘤的基因组表征成为可能，尽管对治疗反应的基因组决定因素在很大程度上仍然未知。我们试图评估横纹肌肉瘤（RMS）临床结局的基因组景观和基因组决定因素。在我们机构使用468基因oncopanel进行基因组分析的29，067例患者中，有87例患有RMS，其中22例为融合阳性。10种最常见的遗传变异与局部控制（LC）、无病生存期（DFS）和总生存期（OS）相关。肿瘤突变负荷（TMB），定义为标准化为测序的兆碱基数的体细胞非同义突变总数，也与临床结局相关。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患者有更多的基因组改变和更高的TMB（平均基因组改变数，6.0 vs 2.9，p=0.007，平均TMB，2.6 vs 1.0，p=0.01）。TP 53的遗传改变与更差的OS相关（p=0.03）。高TMB（定义为最高四分位数，≥2.8）与LC（p=0.05）、DFS（p=0.04）和OS（p=0.01）恶化相关，在控制风险组、融合状态和根据儿科方案接受化疗后，多变量分析仍保持显著性。高TMB与RMS患者的临床结局较差相关。通过进一步验证，TMB和其他基因组分类器可以与传统的临床病理风险因素相结合，以指导风险分层和最终的治疗决策。除了PAX-FOXO 1融合状态外，横纹肌肉瘤（RMS）临床结局的基因组决定因素在很大程度上仍然未知。我们利用我们的机构有针对性的高通量测序工作，以确定87例RMS患者，并将临床结果与基因组改变相关联。我们的研究结果表明，高肿瘤突变负荷（TMB）与RMS的生存率较差相关，独立于其他众所周知的预后和治疗因素，包括风险组和融合状态。在进一步验证之前，TMB可以与传统的临床病理风险因素一起沿着用于改善RMS患者的风险分层和治疗选择。
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). 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 non-synonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes. 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 versus 2.9, p=0.007 and mean TMB, 2.6 versus 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. 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. Genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS) remain largely unknown aside from the PAX-FOXO1 fusion status. We utilized our institutional targeted high throughput sequencing effort to identify 87 patients with RMS, and correlated clinical outcomes with genomic alterations. Our results show that high tumor mutational burden (TMB) is associated with worse survival in RMS, independent of other well-known prognostic and treatment factors including risk group and fusion status. Pending further validation, TMB can be utilized along with traditional clinicopathologic risk factors to improve patient risk stratification and treatment options for RMS.