Exploring preferred amino acid mutations in cancer genes: Applications to identify potential drug targets

Abstract

Somatic mutations developed with missense, silent, insertions and deletions have varying effects on the resulting protein and are one of the important reasons for cancer development. In this study, we have systematically analysed the effect of these mutations at protein level in 41 different cancer types from COSMIC database on different perspectives: (i) Preference of residues at the mutant positions, (ii) probability of substitutions, (iii) influence of neighbouring residues in driver and passenger mutations, (iv) distribution of driver and passenger mutations around hotspot site in five typical genes and (v) distribution of silent and missense substitutions. We observed that R→H substitution is dominant in drivers followed by R→Q and R→C whereas E→K has the highest preference in passenger mutations. A set of 17 mutations including R→Y, W→A and V→R are specific to driver mutations and 31 preferred substitutions are observed only in passenger mutations. These frequencies of driver mutations vary across different cancer types and are selective to specific tissues. Further, driver missense mutations are mainly surrounded with silent driver mutations whereas the passenger missense mutations are surrounded with silent passenger mutations. This study reveals the variation of mutations at protein level in different cancer types and their preferences in cancer genes and provides new insights for understanding cancer mutations and drug development.