Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop tumors, while maintaining normal cerebellar development. Ectopic activation of SHH signaling is sufficient to enforce cerebellar granule cell progenitor–like cell states, which exhibit Pgbd5-dependent expression of distinct DNA repair and neurodevelopmental factors. Mouse medulloblastomas expressing Pgbd5 have increased numbers of somatic structural DNA rearrangements, some of which carry PGBD5-specific sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. This identifies PGBD5 as a medulloblastoma mutator and provides a genetic mechanism for the generation of oncogenic DNA rearrangements in childhood cancer.

中文翻译：

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转座酶衍生的 PGBD5 引起的儿童癌症突变

基因组重排是大多数儿童肿瘤的标志，包括髓母细胞瘤（儿童最常见的脑肿瘤之一），但其原因仍然很大程度上未知。在这里，我们证明 PiggyBac 转座元件衍生 5 (Pgbd5) 在多个发育精确的 Sonic Hedgehog (SHH) 髓母细胞瘤小鼠模型中促进肿瘤发展。大多数 Pgbd5 缺陷小鼠不会产生肿瘤，同时保持正常的小脑发育。 SHH 信号的异位激活足以强化小脑颗粒细胞祖细胞样细胞状态，这些细胞状态表现出不同 DNA 修复和神经发育因子的 Pgbd5 依赖性表达。表达 Pgbd5 的小鼠髓母细胞瘤的体细胞结构 DNA 重排数量增加，其中一些在断点处携带 PGBD5 特异性序列。类似的序列断点反复影响 329 名儿童髓母细胞瘤中已知肿瘤抑制基因和癌基因的体细胞 DNA 重排。这将 PGBD5 鉴定为髓母细胞瘤突变基因，并为儿童癌症中致癌 DNA 重排的产生提供了遗传机制。