p53 Genotypes and Haplotypes Associated With Lung Cancer Susceptibility and Ethnicity.

BACKGROUND: The p53 tumor suppressor protein is important in cell-cycle control, apoptosis, and DNA repair. Mutations in p53 have been associated with inherited cancer susceptibility. Because there is a difference in the risk of lung cancer among different ethnic groups, we examined associations between ethnicity and three polymorphisms in p53 (one exonic and two intronic) and haplotypes for the three loci and risk of lung cancer. We also examined the functionality of the p53 variants in apoptosis and DNA repair. METHODS: In a case-control study, we frequency matched (by age, sex, and ethnicity) 635 lung cancer case patients and 635 control subjects. p53 genotypes and haplotypes at the three polymorphic sites were determined by restriction fragment length polymorphism analysis of lymphocyte DNA. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between genotype or haplotype and lung cancer risk were determined by logistic regression analysis. Apoptosis and DNA repair capacity were measured in 22 lymphoblastoid cell lines to determine the functional effects of the polymorphisms. All statistical tests were two-sided. RESULTS: Genotype and haplotype frequency distributions were strongly dependent on ethnicity; variant allele frequencies were highest in African-Americans (29.1%) and lowest in Mexican-Americans (12.2%). Each of the three polymorphisms was associated with an increased risk of lung cancer among all ethnic groups. Moreover, for all three polymorphisms, increased variant allele copy number was associated with increased risk of lung cancer. Similarly, the variant haplotypes were also associated with an increased risk for lung cancer. Lymphoblastoid cell lines with all wild-type alleles at the three loci had statistically significantly higher apoptotic indices (13.66%, 95% CI = 8.61% to 18.71%) and DNA repair capacity (27.63%, 95% CI = 21.72% to 33.53%) than cell lines with at least one variant allele at all three loci (3.50%, 95% CI = 1.08% to 5.91%; and 17.48%, 95% CI = 7.99% to 26.96%, respectively). CONCLUSIONS: p53 polymorphisms may be associated with increased lung cancer risk and may affect p53 function.

Sulfotransferase (SULT) 1A1 polymorphism as a predisposition factor for lung cancer: a case-control analysis.

SULT1A1 enzyme is a member of the sulfotransferase family that alters biological activities of numerous carcinogenic and mutagenic compounds through sulfation. A genetic polymorphism in the coding region of SULT1A1 gene has been associated with modulated enzyme activity. There is a G-->A nucleotide polymorphism in SULT1A1 gene that codes for an Arg-->His substitution, which results in decreased activity and thermal stability of the SULT1A1 enzyme. Utilizing a case-control study design, we hypothesized that the variant allele of the SULT1A1 gene may be associated with lung cancer risk. The PCR-RFLP assay was used to successfully genotype the SULT1A1*2 allele (variant A-allele) in 463 Caucasian lung cancer cases and 485 frequency matched Caucasian controls. There was an overall significant difference between cases and controls when adjusted by sex and smoking status (adjusted OR=1.41, 95% CI: 1.04-1.91). The adjusted OR was higher for females (OR=1.64, 95% CI: 1.06-2.56) than for males (OR=1.23, 95% CI: 0.80-1.88). Furthermore, the risk was significantly higher in current smokers (OR=1.74, 95% CI: 1.08-2.29) and heavy smokers (OR=1.45, 95% CI: 1.05-2.00). Our results support the hypothesis that a genetic polymorphism in the SULT1A1 gene may be associated with increased lung cancer risk.