title: Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts.
abstract: Mutations in Patched (PTCH) have been associated with tumors characteristic both for children [medulloblastoma (MB) and rhabdomyosarcoma (RMS)] and for elderly [basal cell carcinoma (BCC)]. The determinants of the variability in tumor onset and histology are unknown. We investigated the effects of the time-point and dosage of Ptch inactivation on tumor spectrum using conditional Ptch-knockout mice. Ptch heterozygosity induced prenatally resulted in the formation of RMS, which was accompanied by the silencing of the remaining wild-type Ptch allele. In contrast, RMS was observed neither after mono- nor biallelic postnatal deletion of Ptch. Postnatal biallelic deletion of Ptch led to BCC precancerous lesions of the gastrointestinal epithelium and mesenteric tumors. Hamartomatous gastrointestinal cystic tumors were induced by monoallelic, but not biallelic Ptch mutations, independently of the time-point of mutation induction. These data suggest that the expressivity of Ptch deficiency is largely determined by the time-point, the gene dose and mode of Ptch inactivation. Furthermore, they point to key differences in the tumorigenic mechanisms underlying adult and childhood tumors. The latter ones are unique among all tumors since their occurrence decreases rather than increases with age. A better understanding of mechanisms underlying this ontological restriction is of potential therapeutic value.
authors.affiliation: Institute of Human Genetics, University of Goettingen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Zibat
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
authors.forename: Frauke
authors.initials: F
authors.lastname: Nitzki
authors.forename: Mark
authors.initials: M
authors.lastname: Wijgerde
authors.forename: Anke
authors.initials: A
authors.lastname: Frommhold
authors.forename: Tanja
authors.initials: T
authors.lastname: Heller
authors.forename: Victor
authors.initials: V
authors.lastname: Armstrong
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Julia
authors.initials: J
authors.lastname: Reifenberger
authors.forename: Walter
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn