Medulloblastomas Initiated by Homologous Recombination Defects in Mice.

in The American journal of pathology by Huimei Lu, Yuan Wang, Shipra Chaudhary, Varshita Balaga, Hua Ke, Fuqian Shi, Jingmei Liu, Yangyin Huo, Peter J Romanienko, Bing Xia, Subhajyoti De, Chang S Chan, Zhiyuan Shen

TLDR

  • A study investigating the role of germline mutations in homologous-recombination (HR) genes in medulloblastoma development found that inactivation of HR genes (Brca1, Palb2, and Brca2) induced medulloblastomas, and PARP inhibitors may be effective treatments.

Abstract

Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibited genomic signatures of HR defects. We asked whether ablation of Brca2, Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas. We established conditional knockout mouse models of these HR-genes, and a conditional knockdown of Bccip (shBccip-KD). Deletion of any of these genes led to microcephaly and neurological defects, with Brca1and Bccipproducing the worst. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency, but it exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Bccip/Trp53 deletions failed, despite that shBccip-CKD was highly penetrative, to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. While there were widespread upregulations of cell proliferative pathways, most of the tumors expressed biomarkers of the Sonic Hedgehog subgroup. The MBs developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a PARP inhibitor, but not the ones from shBccip-CKD mice. Our models recapitulate the spontaneous medulloblastoma development with high penetrance and narrow time-window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR defective and proficient tumors.

Overview

  • The study aimed to investigate the role of germline mutations in homologous-recombination (HR) genes in the development of medulloblastomas, the most common malignant brain tumor in children.
  • The researchers used conditional knockout mouse models and a conditional knockdown of Bccip (shBccip-KD) to study the ablation of HR genes (Brca2, Palb2, Brca1, and Bccip) in the mouse brain and their potential to initiate medulloblastomas.
  • The primary objective of the study is to determine whether HR gene mutations can initiate medulloblastomas and to identify potential therapeutic targets for treatment.

Comparative Analysis & Findings

  • The deletion of HR genes (Brca1, Palb2, and Brca2) led to microcephaly and neurological defects, with Brca1 and Bccip-producing the worst outcomes.
  • Trp53 co-deletion partially rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency but had limited impact on Bccip-mice.
  • Inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas, while Bccip/Trp53 deletions failed to induce medulloblastomas despite high penetrance.

Implications and Future Directions

  • The study provides a new insight into the role of HR gene mutations in medulloblastoma development and suggests that PARP inhibitors may be effective treatments for HR-deficient tumors.
  • The study highlights the importance of understanding the genetic mechanisms underlying medulloblastoma development to develop effective targeted therapies.
  • Future studies can explore the use of these mouse models to test therapeutic agents with the ability to differentiate HR-defective and proficient tumors.
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