Phenotypical mapping of TP53 unique missense mutations spectrum in human cancers

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/), 1,297 are identified as unique missense somatic mutations excluding frameshift, intronic, deletion, nonsense, silent, splice, and other unknown mutations. We have comprehensively analyzed all these 1,297 unique missense mutations and created a phenotypical map based on the distribution of mutations 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 mutations are reported in the transactivation and proline-rich domains, 1,065 in the central DNA-binding domains, and 113 in the oligomerization and regulatory domains. Based on the phenotype, these mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutations. The prevalence of these mutations was checked in 71 different types of tissues and found that the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. We correlated the potential impact of mutation in target gene transcription and regulation with nucleosomal DNA and RNA-Pol II complexes. We have discussed the impact of mutation at post-translational modification sites in the structure and function of p53 highlighting the potential therapeutic drug targets with tremendous clinical applications.