Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice

S. Pazzaglia, M. Tanori, M. Mancuso, M. Gessi, E. Pasquali, S. Leonardi, M. A. Oliva, S. Rebessi, V. Di Majo, V. Covelli, F. Giangaspero, A. Saran

Research output: Contribution to journalArticle

Abstract

Inactivation of one Ptc1 allele predisposes humans and mice to spontaneous medulloblastoma development, and irradiation of newborn Ptc1 heterozygous mice results in dramatic increase of medulloblastoma incidence. While a role for loss of wild-type (wt) Ptc1 (LOH) in radiation-induced medulloblastomas from Ptc1neo67/+ mice is well established, the importance of this event in spontaneous medulloblastomas is still unclear. Here, we demonstrate that biallelic Ptc1 loss plays a crucial role in spontaneous medulloblastomas, as shown by high rate of wt Ptc1 loss in spontaneous tumors. In addition, remarkable differences in chromosomal events involving the Ptc1 locus in spontaneous and radiation-induced medulloblastomas suggest distinct mechanisms for Ptc1 loss. To assess when, during tumorigenesis, Ptc1 loss occurs, we characterized cerebellar abnormalities that precede tumor appearance in Ptc1neo67/+ mice. We show that inactivation of only one copy of Ptc1 is sufficient to give rise to abnormal cerebellar proliferations with different degree of altered cell morphology, but lacking potential to progress to neoplasia. Furthermore, we identify biallelic Ptc1 loss as the event causally related to the transition from the preneoplastic stage to full blown medulloblastoma. These results underscore the utility of the Ptc1 neo67/+ mouse model for studies on the mechanisms of medulloblastoma and for development of new therapeutic strategies.

Original languageEnglish
Pages (from-to)5575-5580
Number of pages6
JournalOncogene
Volume25
Issue number40
DOIs
Publication statusPublished - Sep 7 2006

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Keywords

  • Hedgehog
  • Ionizing radiation
  • LOH
  • Medulloblastoma
  • Patched
  • Preneoplasia

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Pazzaglia, S., Tanori, M., Mancuso, M., Gessi, M., Pasquali, E., Leonardi, S., Oliva, M. A., Rebessi, S., Di Majo, V., Covelli, V., Giangaspero, F., & Saran, A. (2006). Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice. Oncogene, 25(40), 5575-5580. https://doi.org/10.1038/sj.onc.1209544