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.
Wu
Xifeng
X
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA. xwu@mail.mdanderson.org
Zhao
Hua
H
Amos
Christopher I
CI
Shete
Sanjay
S
Makan
Nimisha
N
Hong
Waun K
WK
Kadlubar
Fred F
FF
Spitz
Margaret R
MR
D001741:Black or African American; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D016022:Case-Control Studies; D004260:DNA Repair; D004198:Disease Susceptibility; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000208:ethnology* / Q000209:etiology / Q000235:genetics*; D008297:Male; D017058:Mexican Americans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics