title: Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity.
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.
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of General Surgery, Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Surgery, Tumor Biology Program, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zou
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Fang
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019295:Computational Biology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D015203:Reproducibility of Results; D016019:Survival Analysis; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human