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 C57BL͞6J strain background. In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4͞SvJae background are highly resistant to developing astrocytoma. Through analysis of F 1 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 C57BL͞6,129 strain background, these data also provide a powerful example of the potential of these strains to mask interesting gene functions.A strocytoma is a characteristically diffuse tumor of the central nervous system (CNS). Because of its diffuse infiltration, it often cannot be completely resected, leading to a very poor prognosis for patients. Astrocytoma, together with glioblastoma (the highest grade of astrocytoma), accounts for more than three-quarters of all gliomas, making it the most common malignant brain tumor (1). The 5-year survival rate for glioblastoma is Ͻ3%. A better understanding of the genetic risk factors associated with astrocytoma will give insight into the mechanism of astrocytoma initiation and progression and will lead to better screening methods and new targets for therapy.Data from human populations pointing to genetic risk factors for astrocytoma are sparse. Malmer et al. (2) have examined the increased family risk of developing low-vs. high-grade glioma and favor the view that autosomal recessive genes affect astrocytoma risk, although the role of a common environment in familial risk cannot be excluded. Several familial cancer syndromes show an increased risk for astrocytoma, including neurofibromatosis type 1 (NF1) (3, 4) and Li-Fraumeni syndrome (LFS) (5). NF1 patients have a mutation in the NF1 gene (6) (Nf1 in the mouse) and are predisposed to neurofibromas and optic gliomas, with an increased risk for malignant peripheral nerve sheath tumors and diffuse astrocytoma͞glioblastoma (3, 4). Studies of NF1 families have demonstrated a role for modifier genes unlinked to NF1 in the severity of the disease with respect to the numbers of neurofibromas and the presence or absence of optic gliomas (7). Studies of NF1 patients have also shown that patients with optic glioma are more likely to develop CNS tumors such as astrocytoma ...
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