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

Abstract

Background 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. Results 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. Conclusions 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.

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.…”

Oncogene-like addiction to aneuploidy in human cancers

“…The complete dataset for mutual exclusivity and co-occurrence is included in table S1. ( E ) Boxplots displaying the TP53 -mutation phenocopy signature ( 45 ) in cancers from TCGA, split according to whether the cancers harbor a nonsynonymous mutation in TP53 . ( F ) A scatterplot comparing the association between chromosome arm gains and the TP53 -mutation phenocopy signature ( 45 ) in TP53 wild-type cancers from TCGA.…”

“…Cancers with chromosome 1q gains are highlighted in blue. ( G ) Boxplots displaying the TP53 -mutation phenocopy signature ( 45 ) in cancers from TCGA, split according to whether tumors harbor a gain of chromosome 1q. Only TP53 wild-type cancers are included in this analysis.…”

“…5D). Next, we applied a classification algorithm capable of predicting cancers that lack p53 function on the basis of their transcriptional profiles ( 45 ). As expected, cancers from TCGA with nonsynonymous TP53 mutations scored higher with this classifier than cancers with wild-type TP53 (Fig.…”

A study related to the treatment of gastric cancer with Xiang-Sha-Liu-Jun-Zi-Tang based on network analysis

“…STAT3 is a key signaling molecule and transcription factor for gastric mucosal function, and hyperphosphorylation activation of STAT3 promotes inflammation, cell proliferation, and angiogenesis and inhibits programmed cell death, thereby promoting GC development [ 30 ]. TP53 is a common tumor suppressor gene, but it is prone to mutation, and mutant TP53 genes can cause loss of tumor growth inhibition, thus promoting cancer cell proliferation and cell invasion [ 31 ]. MAPK3, MAPK1, and MAPK14 all belong to the mitogen-activated protein kinase class of targets.…”