The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation

Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway andTP53inactivation (∼25% and 10% of cases, respectively). However, mouse models of MB, regardless of their initiating lesions, generally depend uponp53inactivation for rapid onset and high penetrance. The gene encoding the cyclin-dependent kinase inhibitor p18Ink4cis transiently expressed in mouse cerebellar granule neuronal precursor cells (GNPs) as they exit the cell division cycle and differentiate. Coinactivation ofInk4candp53provided cultured GNPs with an additive proliferative advantage, either in the presence or absence of Shh, and induced MB with low penetrance but with greatly increased incidence following postnatal irradiation. In contrast, mice lacking one or two functionalInk4calleles and one copy ofPatched(Ptc1) encoding the Shh receptor rapidly developed MBs that retained wild-typep53. In tumor cells purified from double heterozygotes, the wild-typePtc1allele, but notInk4c, was inactivated. Therefore, when combined withPtc1mutation,Ink4cis haploinsufficient for tumor suppression. Methylation ofINK4C(CDKN2C) was observed in four of 23 human MBs, and p18INK4Cprotein expression was extinguished in 14 of 73 cases. Hence, p18INK4Closs may contribute to MB formation in children.