Prevalence, causes and impact of TP53-loss phenocopying events in human tumors

• Published in: BMC biology Vol. 21; no. 1; p. 92
• Main Authors: Fito-Lopez, Bruno, Salvadores, Marina, Alvarez, Miguel-Martin, Supek, Fran
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-04-2023; BioMed Central; BMC
• Subjects: Amplification; Analysis; Anticancer properties; Antitumor agents; Apoptosis; Association analysis; Biomarkers; Cancer; Cell cycle; Cell Cycle Proteins - metabolism; Copy number; CRISPR; CRISPR screens; Deactivation; Diagnosis; Driver genes; Drug resistance; Drug screening; Gastrointestinal diseases; Gene expression; Gene mutations; Genes; Genes, p53; Genetic aspects; Genetic markers; Genetic screening; Genomes; Genomic analysis; Genomics; Health aspects; Humans; Inactivation; Machine learning; MDM2 protein; Methods; Mutation; Neoplasms - genetics; p53 pathway; p53 Protein; Precision medicine; Prevalence; Prevention; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; PTEN protein; Repressor Proteins - genetics; Risk factors; RNA-mediated interference; Statistical analysis; Transcriptomes; Transcriptomic signature; Tumor cell lines; Tumor evolution; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Spain; Driver genes; Transcriptomic signature; p53 pathway; Tumor evolution; CRISPR screens; Drug resistance; Gene expression
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-023-01595-1

TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized.
We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status.
Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.