Origin of mutations in genes associated with human glioblastoma multiform cancer: random polymerase errors versus...

The etiology of glioblastoma multiforme (GBM), the most serious form of brain cancer, remains obscure, although it has been proposed that cancer risk is a function of random polymerase errors that occur during stem cell division and the resulting mutations in oncogenes and tumor suppressor genes. Analysis of the 8 genes (PTEN, TP53, EGFR, PIK3R1, PIK3CA, NF1, RB1, IDH1) that are mutated in at least 5% of GBM tumors indicates a non-random mutation pattern that reflects a significant role for hydrolytic deamination at CpG sites. The formation of activating mutations in some genes, e.g., IDH1, where a very limited set of mutations are oncogenic, statistically cannot involve random mutagenesis due to polymerase errors that occur during each stem cell replication. Comparison of the in vitro misincorporation tendencies of three replicative polymerases and the "random" mutation pattern in a subset of genes indicates non-polymerase based pathways are involved. Analysis of the mutation patterns shows that chemical deamination that occurs at a slow rate at each CpG is favored over random polymerase errors by a factor of more than 10 million. Therefore, if a truncating nonsense mutation in a tumor suppressor, or an activating missense mutation in an oncogene, can occur due to a C > T base substitution at a CpG sequence, it is highly favored over other mutation pathways.