A new method of identifying glioblastoma subtypes and creation of corresponding animal models.

Glioblastoma (GBM) accounts for up to 50% of brain parenchymal tumors. It is the most malignant type of brain cancer with very poor survival and limited remedies. Cancer subtyping is important for cancer research and therapy. Here, we report a new subtyping method for GBM based on the genetic alterations of CDKN2A and TP53 genes. CDKN2A and TP53 are the most frequently mutated genes with mutation rates of 60 and 30%, respectively. We found that patients with deletion of CDKN2A possess worse survival than those with TP53 mutation. Interestingly, survival of patients with both TP53 mutation and CDKN2A deletion is no worse than for those with only one of these genetic alterations, but similar to those with TP53 mutation alone. Next, we investigated differences in the gene expression profile between TP53 and CDKN2A samples. Consistent with the survival data, the samples with both TP53 mutation and CDKN2A deletion showed a gene expression profile similar to those samples with TP53 mutation alone. Finally, we found that activation of RAS pathway plus Cdkn2a/b silencing can induce GBM, in a similar way to tumor induction by RAS activation plus TP53 silencing. In conclusion, we show that the genetic alterations of CDKN2A and TP53 may be used to stratify GBM, and the new animal models matching this stratification method were generated.