Features Of Cancer-related Point Mutations Are Colocalizde With Exonic Splicing Enhancers (ESE)

Point mutation (missense mutation/nonsense mutation) in the coding sequence of gene is the most common type of mutation causing inherited human diseases. Disease-related point mutations don't just randomly distribute in the coding sequence of genes but site in some specific regions. What has caused disease-related point mutations sited in some specific regions and whether these regions have some particular functional elements of exons? At present, it is still hot research issue in biological field. At the same time, nowadays cancer has become one of the most concerned diseases. Whether cancer-related point mutations also have the feature that enrich in some specific regions in the coding sequence of genes? In this paper, we have analyzed 1,227 cancer-related mutations in 99 human disease-related genes, and identified more than 60% mutations sited positions which also are exonic splicing enhancer (ESE) sites. This finding suggested that cancer-related point mutations strongly colocalized with ESE motifs, so their pathogenic effects are splice related. To understand the potential features of ESE motifs that contained cancer-related point mutations, in the present study, we have evaluated colocalization cancer-related point mutations with putative ESE motifs in 99 genes.These mainly results were as follow:1. The cancer-related point mutations within ESE motifs more preferentially sited within 1nt to 50nt regions at the ends of exons.2. The cancer-related point mutations located inside ESE motifs were more likely to be conservative mutations that might not have effect on the change of the coding protein.3. The sequences of cancer-related point mutations associated-ESE motifs were more conserved than those of known ESE motifs.4. The number of cancer-related point mutations in per CpG inside ESE motifs was approach four times higher than that in CpGs outside ESE motifs, indicated CpG dinucleotides were hot spots for cancer pathogenic point mutations in ESE motifs.In summary, ESE motifs can't correctly bind with SR protein as most of cancer-related point mutations change ESE motifs, and result in exon skipping. Beside, the cancer-related point mutations within ESE motifs more preferentially site at the both ends of exons, this result demonstrates these mutations more easily disrupt exons normal recognition and splice. The two results fully illustrate one of major pathogenic effects of cancer-relate point mutations might be splice related.