Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity

J Xu,B Xu,J Qian,J-Y Fang,H Chen,Y Hu,J Wang,W Zou

doi:10.1038/cddis.2014.75

Abstract

Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF). It is increasingly likely that p53-hotspot mutations may confer different types and magnitudes of GOF, but the evidences are mainly supported by cellular and transgenic animal models. Here we combine large-scale cancer genomic data to characterize the prognostic significance of different p53 mutations in human cancers. Unexpectedly, only mutations on the Arg248 and Arg282 positions displayed significant association with shorter patient survival, but such association was not evident for other hotspot GOF mutations. Gene set enrichment analysis on these mutations revealed higher activity of drug-metabolizing enzymes, including the CYP3A4 cytochrome P450. Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs. Our results suggest that p53 mutations have unequal GOF activities in human cancers, and future evaluation of p53 as a cancer biomarker should consider which mutation is present in the tumor, rather than having comparison between wild-type and mutant genotypes.

Highlights

In addition to its transcription-dependent functions, the p53 protein has been found to function in mitochondria,[9] where it binds to Bcl-XL and induces mitochondrial outer membrane permeabilization (MOMP) and apoptosis.[10]
Genome Atlas (TCGA) patient cohorts that had higher frequency of p53 mutation and adequate patient outcome data. These include breast invasive carcinoma,[23] colorectal cancer,[24] glioblastoma,[25] lung squamous cell carcinoma[26] and ovarian serous cystadenocarcinoma[23]. These data sets include a total number of 2916 cases, and the mutation spectrum of TP53 gene was similar to that reported previously.[27]
To analyze if mutant p53 aggregation[28] or abolished contact with DNA is associated with patient outcome, the patients were classified according to the type of p53 mutations

Summary

Introduction

In addition to its transcription-dependent functions, the p53 protein has been found to function in mitochondria,[9] where it binds to Bcl-XL and induces mitochondrial outer membrane permeabilization (MOMP) and apoptosis.[10]. R248W, R248Q and R282W sit in the binding surface to Bcl-XL11,12 (Figure 1c). It is currently unknown if these ‘Bcl-XL contact’ mutations confer any specific cancerous phenotypes. It is becoming increasingly evident that mutant p53 proteins lose their tumor-suppressor function but some acquire oncogenic gain-of-function (GOF).[1,7,13,14] The most compelling support for GOF comes from mice engineered to harbor some of the hot spot tumor-associated p53 mutations. R175H or R273H showed more spontaneous carcinomas, sarcomas and lymphomas. These mutants increased tumor metastasis, they do not shorten mouse survival time as compared with p53-null background.[15,16] It was found that R248Q mutation could accelerate onset of all tumor types

Methods

Results

Conclusion