High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice

Individuals affected with the Gorlin syndrome inherit a germ-line mutation of the patched (Ptc1) developmental gene and, analogously to Ptc1 heterozygous mice, show an increased susceptibility to spontaneous tumor development. Human and mouse Ptc1 heterozygotes (Ptc1(+/-)) are also hypersensitive to ionizing radiation (IR)-induced tumorigenesis in terms of basal cell carcinoma (BCC) induction. We have analysed the involvement of Ptc1 in the tumorigenic response to a single dose of 3 Gy X-rays in neonatal and adult Ptc1 heterozygous and wild type mice. We report that irradiation dramatically increased the incidence of medulloblastoma development (51%) over the spontaneous rate (7%) in neonatal but not adult Ptc1 heterozygotes, indicating that medulloblastoma induction by IR is subjected to temporal restriction. Analysis of Ptc1 allele status in the tumors revealed loss of the wild type allele in 17 of 18 medulloblastomas from irradiated mice and in two of three spontaneous medulloblastomas. To our knowledge, irradiated newborn Ptc1(+/-) heterozygous mice constitute the first mouse model of IR-induced medulloblastoma tumorigenesis, providing a useful tool to elucidate the molecular basis of medulloblastoma development.