Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. Significance: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.

中文翻译：

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复发难治性儿童实体瘤的基因组学和转录组学分析揭示了不同的分子景观和免疫逃避机制

患有难治性或复发 (R/R) 肿瘤的儿童预后较差。由于驱动 R/R 疾病的基因组基础尚未明确定义，我们在此描述了来自参加 Beat Childhood Cancer Consortium 临床试验的 202 名患者的 R/R 实体瘤的基因组和转录组学景观。肿瘤突变负荷 (TMB) 相对于诊断时未治疗的肿瘤有所升高，三分之一的肿瘤被归类为儿童高 TMB。先前的化疗暴露影响了这些 R/R 肿瘤的突变情况，超过 40% 的肿瘤表现出与铂类或替莫唑胺化疗相关的突变特征，两个肿瘤表现出治疗相关的超突变。免疫基因组学分析发现了新抗原和 MHC I 类表达的异质模式以及普遍缺乏免疫浸润。转录分析和功能基因集富集分析确定了与发育、免疫信号和细胞信号通路相关的交叉病理学簇。虽然这些 R/R 肿瘤的情况反映了诊断时相应的未治疗肿瘤的情况，但观察到重要的例外情况，提示肿瘤进化、治疗耐药机制和治疗的诱变病因。意义：肿瘤异质性、化疗暴露和肿瘤进化有助于分子概况和增加的突变负担，这些发生在治疗难治性和复发性儿童实体瘤中。转录分析和功能基因集富集分析确定了与发育、免疫信号和细胞信号通路相关的交叉病理学簇。虽然这些 R/R 肿瘤的情况反映了诊断时相应的未治疗肿瘤的情况，但观察到重要的例外情况，提示肿瘤进化、治疗耐药机制和治疗的诱变病因。意义：肿瘤异质性、化疗暴露和肿瘤进化有助于分子概况和增加的突变负担，这些发生在治疗难治性和复发性儿童实体瘤中。转录分析和功能基因集富集分析确定了与发育、免疫信号和细胞信号通路相关的交叉病理学簇。虽然这些 R/R 肿瘤的情况反映了诊断时相应的未治疗肿瘤的情况，但观察到重要的例外情况，提示肿瘤进化、治疗耐药机制和治疗的诱变病因。意义：肿瘤异质性、化疗暴露和肿瘤进化有助于分子概况和增加的突变负担，这些发生在治疗难治性和复发性儿童实体瘤中。虽然这些 R/R 肿瘤的情况反映了诊断时相应的未治疗肿瘤的情况，但观察到重要的例外情况，提示肿瘤进化、治疗耐药机制和治疗的诱变病因。意义：肿瘤异质性、化疗暴露和肿瘤进化有助于分子概况和增加的突变负担，这些发生在治疗难治性和复发性儿童实体瘤中。虽然这些 R/R 肿瘤的情况反映了诊断时相应的未治疗肿瘤的情况，但观察到重要的例外情况，提示肿瘤进化、治疗耐药机制和治疗的诱变病因。意义：肿瘤异质性、化疗暴露和肿瘤进化有助于分子概况和增加的突变负担，这些发生在治疗难治性和复发性儿童实体瘤中。