Mutational processes shape the landscape of TP53 mutations in human cancer

Abstract

Unlike most tumor suppressor genes, the most common genetic alterations in TP53 are missense mutations ^{1, 2} . Mutant p53 protein is often abundantly expressed in cancers, and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models ^{3– 8} . To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic pair of TP53-wild-type and -null cell lines. We found that loss or dominant-negative inhibition of p53 function reliably enhanced cellular fitness. By integrating these data with the COSMIC mutational signatures database ^{9, 10} , we developed a statistical model that describes the TP53 mutational spectrum as a function of the baseline probability of acquiring each mutation and the fitness advantage conferred by attenuation of p53 activity. Collectively, these observations show that widely-acting and tissue-specific mutational processes combine with phenotypic selection to dictate the frequencies of recurrent TP53 mutations.