Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
Cancer Discov. 2024 Jun 3;14(6):953-964. doi: 10.1158/2159-8290.CD-23-1186.
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.
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. See related commentary by Pacyna and Nangalia, p. 900. This article is featured in Selected Articles from This Issue, p. 897.
儿科癌症是罕见疾病，在发育年龄期间发生第二种恶性肿瘤且无已知种系易感性的儿童极为罕见。我们提出了四个这样的临床病例，并通过肿瘤和正常样本的全基因组和纠错超深度双测序，探索了四个儿童中第二种恶性肿瘤的起源，揭示了不同的发展途径。细胞毒性治疗的暴露与继发性急性髓细胞白血病的出现有关。在另一个孩子的两种实体恶性肿瘤中，早期在胚胎发育过程中获得的常见体细胞突变是驱动因素。在两种情况下，两个肿瘤均来自胚胎发生过程中完全独立的克隆分化。重要的是，我们证明，在这些儿童中，铂类治疗导致的每天暴露的突变数量至少比正常组织的老化多一个数量级。
使用全基因组和纠错超深度双测序，我们揭示了四个儿童中第二种肿瘤的不同起源。我们还在暴露个体的 10 个正常组织中发现了与铂相关的突变，这突出了细胞毒性治疗的使用可能对癌症幸存者产生的影响。请参阅 Pacyna 和 Nangalia 的相关评论，第 900 页。本文是本期精选文章的一部分，第 897 页。
