Features of missense/nonsense mutations in exonic splicing enhancer sequences from cancer-related human genes

Missense/nonsense mutations, which are related to pathogenic conditions, are regarded as pathogenic mutations. The features of pathogenic mutations in gene coding regions are still unclear. To explore the pathogenic mutation features of human cancer-related genes, 1227 missense/nonsense mutations from 99 human cancer-related genes were analyzed. We found that the mutability in exonic splicing enhancers (ESEs) is less than that outside ESEs. CpG sites are more enriched in ESEs than outside ESEs. Decrease of mutability in ESEs is much larger than that outside ESEs upon removal of CpG mutations since CpG is more mutable. In addition, the bases in ESEs are prone to undergo C→T/G→A mutations. What is more, mutations in ESEs were preferentially located within 50 nt flanking the short exons (≤250 nt), and tend to be of conservative type with minimum effect on the protein structure. Finally, nonsense mutation located in ESEs might be related to Nonsense Mediated Decay (NMD) pathway. In conclusion, this study explored the features of pathogenic mutations of human cancer-related genes.

► Pathogenic mutations inside ESEs are less mutable.
► ESEs seem to be prone to C→T and G→A mutations.
► Colocalization of CpG dinucleotides with pathogenic mutations inside ESEs.
► Mutations inside ESEs were preferentially located within exonic boundaries.