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Cell Death Dis. 2014 Mar 6;5:e1108. doi: 10.1038/cddis.2014.75.

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

Author information

1
State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Department of General Surgery, Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
3
Department of Surgery, Tumor Biology Program, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.

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.

PMID:
24603336
PMCID:
PMC3973211
DOI:
10.1038/cddis.2014.75
[Indexed for MEDLINE]
Free PMC Article

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