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

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 radiationinduced medulloblastomas from Ptc1 neo67/ þ 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 Ptc1 neo67/ þ 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/ þ mouse model for studies on the mechanisms of medulloblastoma and for development of new therapeutic strategies.

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

“…6A). Regardless of radiation dose, we found a marked heterogeneity of LOH patterns in MBs developed after embryonic irradiation (E13.5 and E16.5) compared to tumors developed in mice irradiated as newborns (typically showing large chr13 interstitial deletions [31]). In mice irradiated at E13.5 only 43% (3/7) of the tumors showed typical interstitial deletions, while 28% (2/7) displayed large terminal losses and 28% (2/7) showed loss of the whole chr13.…”

Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo

“…A slower repair kinetics may contribute to a residual low level of unrepaired DSBs, providing opportunity for loss of heterozygosity of critical genetic regions. Ptch1 loss of heterozygosity is indeed a crucial event for Ptch1-associated tumorigenesis in cerebellum (Pazzaglia et al, 2006).…”

Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

“…PTCH is a Sonic Hedgehog (SHH) receptor and negative regulator of the pathway causing predisposition to childhood medulloblastoma (43). Ptch1 +/-mutant mice develop cerebellar tumours resembling human medulloblastoma which is accelerated when irradiated as neonates (44). Partial body irradiation of neonatal Ptch1 +/-mice was shown to significantly increase the occurrence of medulloblastoma compared to control animals, accompanied with increased DNA damage and apoptosis in the cerebellum.…”