Nucleotide Substitution Biases in Related Cancer Driver Genes

Nucleotide substitutions are common in cancer cells, and they occur in both protein coding regions and non-coding regions (5' and 3' UTRs and introns). Although substitutions in non-coding regions have the potential to alter gene expression, it is the alteration of coding regions that affects protein function and has the most drastic effect on cellular transformation. Mutations in certain genes (e.g., TP53, KRAS) are common to nearly all cancers, but most cancers are characterized by specific gene mutation signatures. In this report, we investigated nucleotide substitution signatures in coding regions of the top 25 most frequently mutated genes in multiple human cancers. The goal was to examine whether unique nucleotide substitution biases are associated with various cancers. A pan-cancer analysis showed that the most altered nucleotide is guanine, which is biased towards G->A transitions. A per-cancer analysis identified ten cancers with biased substitutions in certain genes. Some of these biases were expected (e.g., KRAS in gastrointestinal cancers or JAK2 in blood cancers). Our analysis revealed biased signature substitutions in 17 genes, of which 14 were characterized as drivers and constituted a closely related set of cell cycle regulators. We conclude that nucleotide substitution biases contribute to specific alterations in cancer genes that produce cellular transformation. Principle component analysis of nucleotide substitutions shows that most cancers cluster together, meaning that they have similar nucleotide changes. However, certain cancers, most notably lung, pancreas, and blood cancers, can be differentiated from each other based on specific nucleotide signatures. Thus, nucleotide substitution patterns can be used to differentiate between some cancers.