Prevalence, causes and impact ofTP53-loss phenocopying events in human tumors

Abstract

AbstractTP53is 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 phenocopyTP53loss: they are likely deficient in the activity of the p53 pathway, while not bearing obviousTP53inactivating mutations. While some of these are explained by amplifications in the known phenocopying genesMDM2, MDM4andPPM1D, others are not. An analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additionalTP53-loss phenocopying gene,USP28. Deletions inUSP28are associated with aTP53functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and are comparable toMDM4amplifications in terms of effect size. Additionally, in the known CNA segments harboringMDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost theTP53functional inactivation effect. An analysis using the phenocopy scores suggests thatTP53(in)activity commonly modulates associations between anticancer drug effects and relevant genetic markers, such asPIK3CAandPTENmutations, 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 onTP53functional status.