Phenotypical mapping of TP53 unique missense mutations spectrum in human cancers

Abstract

The p53 tumor suppressor is one of the most mutated genes responsible for tumorigenesis in most human cancers. Out of 29,891 genomic mutations reported in the TP53 Database (https://tp53.isb-cgc.org/), 1297 are identified as unique missense somatic mutants excluding frameshift, intronic, deletion, nonsense, silent, splice and other unknown mutations. we have comprehensively analyzed all these 1297 unique missense mutations and created a phenotypical map based on the distribution of mutants in each domain, the functional state of the protein, and their occurrence in different types of tissues and organs. Our mutation map shows that almost 118 unique missense mutants are reported in the transactivation domain (TADs) and proline-rich domain (PRR), 1,065 in the central DNA-binding domain (DBD), and 113 in the oligomerization (OD) and regulatory domain (RD). Based on the phenotype these 1297 mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutants. The prevalence of all these mutations was checked in 71 different types of tissues and found the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. The propensity calculation of mutation for each amino acid in p53, showed Proline, Arginine, and Leucine/Glutamic acid are the most frequently mutated residues in the TAD domain, DBD, and TD respectively. We have correlated the impact of these mutations in the structure and function of p53 and highlighted the TP53 unique missense mutants that can be a potential therapeutic drug target with tremendous clinical applications.