title: p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use.
abstract: Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked > 30 pack-years as compared to tumors from patients who smoked < or = 30 pack-years (OR = 2.8; CI = 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [+] genotype (OR = 6.0; CI = 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University, School of Medicine, Philadelphia, PA 19140, USA. plazarus@vm.temple.edu
authors.forename: P
authors.initials: P
authors.lastname: Lazarus
authors.forename: S N
authors.initials: SN
authors.lastname: Sheikh
authors.forename: Q
authors.initials: Q
authors.lastname: Ren
authors.forename: S P
authors.initials: SP
authors.lastname: Schantz
authors.forename: J C
authors.initials: JC
authors.lastname: Stern
authors.forename: J P
authors.initials: JP
authors.lastname: Richie
authors.forename: J Y
authors.initials: JY
authors.lastname: Park
mesh_terms: D001564:Benzo(a)pyrene / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D005091:Exons; D016158:Genes, p53; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D009062:Mouth Neoplasms / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009602:Nitrosamines / Q000633:toxicity; D010947:Plants, Toxic; D011110:Polymorphism, Genetic; D012907:Smoking; D014026:Nicotiana
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D009602:Nitrosamines; D001564:Benzo(a)pyrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase