The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ∼30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ∼10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression.
Submitter: Connie Wang
Submission Date: July 12, 2018, 11:33 a.m.
|Number of data points||2950|
|Proteins||Cellular tumor antigen p53|
|Assays/Quantities/Protocols||Experimental Assay: HCT116 In Vivo Enrichment ; Experimental Assay: Number of occurrences in the IARC p53 database ; Experimental Assay: H1299 Relative Fitness Score|
|Libraries||H1299 Relative Fitness Score (Protein Variants) ; HCT116 In Vivo Enrichment|