Mutational processes shape the landscape of TP53 mutations in human cancer.

Nat Genet
Authors
Keywords
Abstract

Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models. 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 wild-type p53 function reliably enhanced cellular fitness. By integrating these data with the Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures database, 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.

Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
10
Pages
1381-1387
Date Published
2018 10
ISSN
1546-1718
DOI
10.1038/s41588-018-0204-y
PubMed ID
30224644
PubMed Central ID
PMC6168352
Links
Grant list
T32 GM007226 / GM / NIGMS NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States
K08 CA218420 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States