Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin, Berlin, Germany.
German Cancer Consortium, Berlin, Germany.
JCI Insight. 2018 Oct 18;3(20):123172. doi: 10.1172/jci.insight.123172.
Our understanding of the molecular pathogenesis of childhood cancers has advanced substantially, but their fundamental causes remain poorly understood. Recently, multiple mechanisms of DNA damage and repair have been associated with mutations observed in human cancers. Here, we review the physiologic functions and oncogenic activities of transposable genetic elements. In particular, we focus on the recent studies implicating DNA transposases RAG1/2 and PGBD5 as oncogenic mutators that promote genomic rearrangements in childhood leukemias and solid tumors. We outline future studies that will be needed to define the contributions of transposons to mutational processes that become dysregulated in cancer cells. In addition, we discuss translational approaches, including synthetic lethal strategies, for identifying and developing improved clinical therapies to target oncogenic transposons and transposases.
我们对儿童癌症的分子发病机制的理解已经有了很大的进展，但它们的根本原因仍不清楚。最近，多种 DNA 损伤和修复机制与人类癌症中观察到的突变有关。在这里，我们回顾转座遗传元件的生理功能和致癌活性。特别是，我们关注最近的研究，这些研究表明 RAG1/2 和 PGBD5 等 DNA 转座酶是致癌突变剂，可促进儿童白血病和实体瘤中的基因组重排。我们概述了未来需要进行的研究，以确定转座子在癌症细胞中失调的突变过程中的贡献。此外，我们还讨论了转化方法，包括合成致死策略，以确定和开发改善的临床治疗方法，以靶向致癌转座子和转座酶。
