Susceptibility to Astrocytoma in Mice Mutant for Nf1 and Trp53 Is Linked to Chromosome 11 and Subject to Epigenetic Effects

Astrocytoma is the most common malignant brain tumor in humans. Loss of the p53 signaling pathway and up-regulation of the ras signaling pathway are common during tumor progression. We have shown previously that mice mutant for Trp53 and Nf1 develop astrocytoma, progressing to glioblastoma, on a C57...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 35; pp. 13008 - 13013
Main Authors Reilly, Karlyne M., Tuskan, Robert G., Christy, Emily, Loisel, Dagan A., Ledger, Jeremy, Bronson, Roderick T., Smith, C. Dahlem, Tsang, Shirley, Munroe, David J., Jacks, Tyler, Vogelstein, Bert
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 31.08.2004
National Acad Sciences
Subjects
Alleles
Animals
Apoptosis Regulatory Proteins
Astrocytoma
Astrocytoma - genetics
Astrocytoma - pathology
Biological Sciences
Carrier Proteins - genetics
Crosses, Genetic
Cytoplasmic inheritance
Female
Genetic inheritance
Genetic Linkage
Genetic mutation
Genetic Predisposition to Disease
Heat-Shock Proteins - genetics
Inbred strains
Inbreeding
Male
Medical genetics
Mice
Models, Genetic
Neurofibromin 1 - genetics
Tumors
Online AccessGet full text

Cover

More Information
Summary:Astrocytoma is the most common malignant brain tumor in humans. Loss of the p53 signaling pathway and up-regulation of the ras signaling pathway are common during tumor progression. We have shown previously that mice mutant for Trp53 and Nf1 develop astrocytoma, progressing to glioblastoma, on a C57BL/6J strain background. In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4/SvJae background are highly resistant to developing astrocytoma. Through analysis of F1progeny, we demonstrate that susceptibility to astrocytoma is linked to chromosome 11, and that the modifier gene(s) responsible for differences in susceptibility is closely linked to Nf1 and Trp53. Furthermore, this modifier of astrocytoma susceptibility is itself epigenetically modified. These data demonstrate that epigenetic effects can have a strong effect on whether cancer develops in the context of mutant ras signaling and mutant p53, and that this mouse model of astrocytoma can be used to identify modifier phenotypes with complex inheritance patterns that would be unidentifiable in humans. Because analysis of gene function in the mouse is often performed on a mixed C57BL/6, 129 strain background, these data also provide a powerful example of the potential of these strains to mask interesting gene functions.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Edited by Bert Vogelstein, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, and approved July 9, 2004
This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: kreilly@ncifcrf.gov.
Abbreviations: NF1, neurofibromatosis type 1; SSLP, simple sequence length polymorphism; NPcis, Nf1;Trp53cis; B6, C57BL/6J; 129, 129S4/SvJae; A, A/J; DB, DBA/2J; CB, CBA/J; 129S1, 129S1/SvImJ; 129X1, 129X1/SvJ; SNP, single nucleotide polymorphism; chr, chromosome; WHO, World Health Organization; NCBI, National Center for Biotechnology Information; dbSNP, Single Nucleotide Polymorphism Database.
Data deposition: The SNP data reported in this paper have been deposited in the NCBI Single Nucleotide Polymorphism Database (dbSNP) (dbSNP ID nos. 28476647-28476655; see also Table 4, which is published as supporting information on the PNAS web site).
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401236101