Prevalence, causes and impact ofTP53-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.

Oncogene-like addiction to aneuploidy in human cancers

“…(E) Boxplots displaying the TP53-mutation phenocopy signature 57 in cancers from the TCGA, split based on whether the cancers harbor a non-synonymous mutation in TP53.…”

“…(F) A scatterplot comparing the association between chromosome arm gains and the TP53-mutation phenocopy signature 57 in TP53-wildtype cancers from TCGA. Cancers with chromosome 1q gains are highlighted in blue.…”

“…(G) Boxplots displaying the TP53-mutation phenocopy signature 57 in cancers from the TCGA, split based on whether tumors harbor a gain of chromosome 1q. Only TP53-wildtype cancers are included in this analysis.…”

“…Put differently, while chromosome 1q gains and TP53 mutations are separately very common in cancer, individual tumors develop both 1q gains and TP53 mutations significantly less often than expected by chance (P < 10 - 39 , Fisher’s exact test; Table S1). Next, we applied a recently-described classification algorithm capable of predicting cancers that lack p53 function based on their transcriptional profiles 57 . As expected, cancers from the TCGA with non-synonymous TP53 mutations scored significantly higher with this classifier than cancers with wild-type TP53 (Fig.…”

Variable efficiency of nonsense-mediated mRNA decay across human tissues, tumors and individuals

“…For instance, for 61.8% of LUAD samples with 1q gain, 67% of those also had a lower ETG iNMDeff than the median ETG iNMDeff across the LUAD samples with no gain. These 1q gains were proposed to be selected because they increase dosage of the MDM4 oncogene 63 , whose product downregulates the p53 protein post-translationally 64 , hence phenocopying the loss of the tumor suppressor TP53 65 . However, there are other oncogenes in chr 1q that might be driving this gain.…”