RGD Reference Report - Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts. - Rat Genome Database

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Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts.

Authors: Zibat, Arne  Uhmann, Anja  Nitzki, Frauke  Wijgerde, Mark  Frommhold, Anke  Heller, Tanja  Armstrong, Victor  Wojnowski, Leszek  Quintanilla-Martinez, Leticia  Reifenberger, Julia  Schulz-Schaeffer, Walter  Hahn, Heidi 
Citation: Zibat A, etal., Carcinogenesis. 2009 Jun;30(6):918-26. doi: 10.1093/carcin/bgp068. Epub 2009 Mar 25.
RGD ID: 150523834
Pubmed: PMID:19321799   (View Abstract at PubMed)
DOI: DOI:10.1093/carcin/bgp068   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PTCH1HumanGastrointestinal Neoplasms  ISOPtch1 (Mus musculus) RGD 
Ptch1RatGastrointestinal Neoplasms  ISOPtch1 (Mus musculus) RGD 
Ptch1MouseGastrointestinal Neoplasms  IMP  RGD 
PTCH1Humanmedulloblastoma  ISOPtch1 (Mus musculus) RGD 
Ptch1Ratmedulloblastoma  ISOPtch1 (Mus musculus) RGD 
Ptch1Mousemedulloblastoma  IMP  RGD 
PTCH1Humanrhabdomyosarcoma  ISOPtch1 (Mus musculus) RGD 
Ptch1Ratrhabdomyosarcoma  ISOPtch1 (Mus musculus) RGD 
Ptch1Mouserhabdomyosarcoma  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ptch1  (patched 1)

Genes (Mus musculus)
Ptch1  (patched 1)

Genes (Homo sapiens)
PTCH1  (patched 1)


Additional Information