Journal Article

Time-point and dosage of gene inactivation determine the tumor spectrum in conditional <i>Ptch</i> knockouts

Arne Zibat, Anja Uhmann, Frauke Nitzki, Mark Wijgerde, Anke Frommhold, Tanja Heller, Victor Armstrong, Leszek Wojnowski, Leticia Quintanilla-Martinez, Julia Reifenberger, Walter Schulz-Schaeffer and Heidi Hahn

in Carcinogenesis

Volume 30, issue 6, pages 918-926
Published in print June 2009 | ISSN: 0143-3334
Published online March 2009 | e-ISSN: 1460-2180 | DOI:
Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts

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  • Clinical Cytogenetics and Molecular Genetics


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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.

Journal Article.  5735 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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