"Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects".

Karlyne M. Reilly *^{, @}, Robert G. Tuskan *, Emily Christy ^{1, 2}, Dagan A. Loisel ^{1, 2}, Jeremy Ledger ¹, Roderick T. Bronson ¶, C. Dahlem Smith ||, Shirley Tsang **, David J. Munroe ** and Tyler Jacks ^{1, 2},

*Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702;
¹ Department of Biology and Center for Cancer Research and ² Howard Hughes Medical Institute,    Massachusetts Institute of Technology, Cambridge, MA 02169;
¶Department of Pathology, Harvard Medical School, Boston, MA 02115;
Laboratories of ||Animal Sciences Program and **MolecularTechnology, Science Applications International Corporation, Frederick, MD 21702

^@ To whom correspondence should be addressed. E-mail:  kreilly@ncifcrf.gov

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 F₁ progeny, 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.

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). http://www.pnas.org/cgi/content/full/0401236101/DC1

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