Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects

Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeut ics. Mouse models of astrocytoma have been designed to express oncogenic pr oteins in astrocytes, but have had limited success due to low tumour penetr ance or limited tumour progression(1-3). We present here a mouse model of a strocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp5 3. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas(4,5). The TP53 tumour suppressor is often mutated in a subset of astrocytomas tha t develop at a young age and progress slowly to glioblastoma (termed second ary glioblastomas, in contrast to primary glioblastomas that develop rapidl y de novo(6-10)). This mouse model shows a range of astrocytoma stages, fro m low-grade astrocytoma to glioblastoma multiforme, and may accurately mode l human secondary glioblastoma involving TP53 loss. This is the first repor ted mouse model of astrocytoma initiated by loss of tumour suppressors, rat her than overexpression of transgenic oncogenes.