Childhood cancer mutagenesis caused by transposase-derived PGBD5 Journal Article
| Authors: | Yamada, M.; Keller, R. R.; Gutierrez, R. L.; Cameron, D.; Suzuki, H.; Sanghrajka, R.; Vaynshteyn, J.; Gerwin, J.; Maura, F.; Hooper, W.; Shah, M.; Robine, N.; Demarest, P.; Bayin, N. S.; Zapater, L. J.; Reed, C.; Hébert, S.; Masilionis, I.; Chaligne, R.; Socci, N. D.; Taylor, M. D.; Kleinman, C. L.; Joyner, A. L.; Raju, G. P.; Kentsis, A. |
| Article Title: | Childhood cancer mutagenesis caused by transposase-derived PGBD5 |
| 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. © 2024 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | child; genetics; mouse; animal; metabolism; animals; mice; sonic hedgehog protein; hedgehog proteins; transcription factor; transcription factors; dna; brain; tumors; medulloblastoma; genomics; genome; mammals; cerebellar neoplasms; mutagenesis; diseases; dna sequences; brain tumors; cell signaling; cerebellum tumor; oncogenic viruses; transposase; transposases; transposable elements; tumor development; humans; human; breakpoint; piggybac; childhood cancers; sonic hedgehogs; pgbd5 protein, human |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 12 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-03-01 |
| Start Page: | eadn4649 |
| Language: | English |
| DOI: | 10.1126/sciadv.adn4649 |
| PUBMED: | 38517960 |
| PROVIDER: | scopus |
| PMCID: | PMC10959420 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Alex Kentsis -- Source: Scopus |
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