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Childhood cancer mutagenesis caused by transposase-derived PGBD5.
- Source :
-
Science advances [Sci Adv] 2024 Mar 22; Vol. 10 (12), pp. eadn4649. Date of Electronic Publication: 2024 Mar 22. - Publication Year :
- 2024
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 2375-2548
- Volume :
- 10
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Science advances
- Publication Type :
- Academic Journal
- Accession number :
- 38517960
- Full Text :
- https://doi.org/10.1126/sciadv.adn4649