Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children. Significance: Using whole-genome and error-correcting ultra-deep duplex sequencing, we uncover different origins for second neoplasms in four children. We also uncover the presence of platinum-related mutations across 10 normal tissues of exposed individuals, highlighting the impact that the use of cytotoxic therapies may have on cancer survivors.

中文翻译：

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儿童第二恶性肿瘤的起源和化疗在正常组织中的突变足迹

儿童癌症是罕见疾病，没有已知种系易感条件的儿童在发育年龄期间发生第二种恶性肿瘤的情况极为罕见。我们介绍了四个这样的临床病例，并通过对肿瘤和正常样本进行全基因组和纠错超深双链测序，我们探索了四个儿童的第二种恶性肿瘤的起源，揭示了不同的发展途径。细胞毒性疗法的暴露与继发性急性髓性白血病的出现有关。胚胎发育早期获得的一种常见体细胞突变是另一个儿童患两种实体恶性肿瘤的驱动因素。在两个案例中，这两个肿瘤是由胚胎发生过程中完全独立的克隆发展而来的。重要的是，我们证明，与这些儿童正常组织的衰老相比，铂类疗法每天的暴露造成的突变至少多一个数量级。意义：利用全基因组和纠错超深双链测序，我们发现了四个儿童中第二种肿瘤的不同起源。我们还发现暴露个体的 10 种正常组织中存在与铂相关的突变，强调了细胞毒性疗法的使用可能对癌症幸存者产生的影响。