A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation

The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot'' codons, which account for only similar to 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 similar to 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.

Errata: Table S3 of this manuscript as originally published accidentally displayed the non-normalized RFS values for p53 protein variants. This has been corrected in the online supplemental information, which now displays the RFS values after normalization, performed as described under Computational Analysis in STAR Methods. This correction has no impact on the conclusions drawn from this table (the correlation between the originally published and the corrected values is 0.993). The authors deeply regret this error.