Medulloblastomas Initiated by Homologous Recombination Defects in Mice
Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can...
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| Published in: | The American journal of pathology Vol. 194; no. 11; pp. 2007 - 2022 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Elsevier Inc
01-11-2024
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| Online Access: | Get full text |
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| Summary: | Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibit genomic signatures of HR defects. Whether ablation of Brca2 and Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas was explored here. Conditional knockout mouse models of these HR genes and a conditional knockdown of Bccip (shBccip-KD) were established. Deletion of any of these genes led to microcephaly and neurologic defects, with Brca1– and Bccip– producing the worst defects. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but exhibited limited impact on Bccip– mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Despite shBccip-CKD being highly penetrative, Bccip/Trp53 deletions failed to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. Although there were widespread up-regulations of cell proliferative pathways, most of the tumors expressed biomarkers of the sonic hedgehog subgroup. The medulloblastomas developed from Brca1–, Palb2–, and Brca2– mice were highly sensitive to a poly (ADP-ribose) polymerase inhibitor but not the ones from shBccip-CKD mice. These models recapitulate the spontaneous medulloblastoma development with high penetrance and a narrow time window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR-defective and HR-proficient tumors. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0002-9440 1525-2191 1525-2191 |
| DOI: | 10.1016/j.ajpath.2024.07.018 |