Mutational processes shape the landscape of TP53 mutations in human cancer

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.

A quantitative model to predict pathogenicity of missense variants in the TP53 gene

“…Outcomes were reported as the relative enrichment (Z score) of individual variants under the selective conditions, which again allowed comparison to the output of the model. In a conservative approach to infer LOF, the cut‐off selected was −0.21 for etoposide assays, which showed the best separation between silent and common cancer missense variants as reported in the published data (Figure f in Giacomelli et al, ).…”

“…Variants classified as pathogenic or likely pathogenic by the model were associated with earlier age of cancer onset (including a greater proportion of pediatric cancers), and were enriched in Classic LFS probands and depleted in a cohort of cancer-free women over 70 years. When compared to the output of reported functional assays, the majority of variants classified as pathogenic or likely pathogenic were nonfunctional in transactivation yeast assays (Kato et al, 2003), showed disruption of antiproliferative function/LOF (Giacomelli et al, 2018;Kotler et al, 2018), or reduced activity in the mammalian clonogenic survival assays developed in this study.…”

“…Giacomelli et al, also performed a recent systematic analysis of almost all possible single nucleotide variants in the full length TP53 sequence, using different conditions in a human cell model to independently assess the fitness advantage conferred by loss‐of‐function (LOF). Outcomes were reported as the relative enrichment (Z score) of individual variants under the selective conditions, which again allowed comparison to the output of the model.…”

“…3.3 | Clinical information correlates with variant pathogenicity assigned using the quantitative model (Kato et al, 2003) 54.6% ≤20% activity 1.1% ≤20% activity Antiproliferative function (Kotler et al, 2018) 76.7% disruptive function 3.6% disruptive function LOF (Giacomelli et al, 2018) 74.4% LOF 11.1% LOF Clonogenic survival assays 90.9% disrupted function 0% disrupted function ClinVar 87.1% "P" or "LP" 0% "P" or "LP" than VUS was assigned, were classified as P/LP. The discordant variant was p.Asn235Ser, with functional transactivation class and 55 alleles in gnomAD.…”

A novel androgen‐reduced prostate‐specific lncRNA, PSLNR, inhibits prostate‐cancer progression in part by regulating the p53‐dependent pathway

“…TP53 is one of the most well‐studied tumor‐suppressor genes. However, TP53 mutations or deletions are present in nearly 50% of human cancers and primarily result in impaired tumor‐suppressor function . Our bioinformatic studies showed that PSLNR was significantly involved in the regulation of cell proliferation, apoptosis, and the p53 signaling pathway.…”