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

Abstract

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 from trans-acting alterations -- from gene expression patterns. We apply this approach to transcriptomes of ~8,000 tumors and ~1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines 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 are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, others are not. An analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional 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 are comparable to MDM4 amplifications in terms of effect size. Additionally, in the known CNA segments harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect. An analysis using the phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and relevant genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a relevant interacting factor in personalized medicine studies. As a resource, we provide the drug-marker associations that differ depending on TP53 functional status.