We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.

中文翻译：

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分层医学儿科：游离 DNA 和连续肿瘤测序可识别亚型特异性癌症演变和表观遗传状态


我们分析了来自儿童复发和进展性实体瘤患者的匹配诊断复发肿瘤组织和配对血浆衍生的游离 DNA （cfDNA） 的大型异质性队列。组织和 cfDNA 测序结果是一致的，如果存在足够的循环肿瘤来源的 DNA （ctDNA），则后者捕获的突变等位基因谱更广，肿瘤内异质性更高。连续肿瘤测序确定了推定的复发驱动因素，表观遗传驱动因素的改变是一个常见特征。与表观遗传改变是许多儿童癌症的常见驱动因素保持一致，cfDNA 的片段组学分析确定了染色质中可获得的肿瘤特异性表观遗传状态和转录因子结合位点。本研究利用了侵袭性儿童恶性肿瘤的大型且注释良好的基因组数据集，确定了儿童癌症复发的基因组和表观遗传驱动因素，并强调了 cfDNA 分析在捕获肿瘤内异质性和癌细胞表观遗传状态方面的强大性和实用性。