Lung cancer is a multigenic disease where one variant single nucleotide polymorphism may have only a modest independent effect on the disease phenotype, yet in aggregate, multiple biologically relevant single nucleotide polymorphisms may provide a more accurate representation of risk. Polymorphisms in members of the p53 family, such as p53 and p73, that have a functional relevance would be predicted to contribute to the disease phenotype. In this analysis, we used genotype data from 863 lung cancer cases and 852 healthy controls to test for multigenetic effects of polymorphisms at p53 exon 4, introns 3 and 6, and at p73 exon 2. All individuals in this analysis were self-reported non-Hispanic Caucasians. When the p73 and p53 variant alleles were combined and analyzed as a continuous variable, there was a 13% increase [odds ratios (OR), 1.13; 95% confidence intervals (CI), 1.05-1.21] in lung cancer risk for each additional variant allele. Furthermore, when the number of variant alleles was categorized into three groups (zero, one to three, and four or more variants), there was evidence of a gene-dosage effect with increased risks for individuals with one to three variants (OR, 1.30; 95% CI, 1.05-1.61) and four or more variants (OR, 1.78; 95% CI, 1.23-2.56). When the data were stratified by smoking status, an increased risk for lung cancer was evident only in current (OR, 2.32; 95% CI, 1.25-4.33) and former smokers (OR, 1.73; 95% CI, 1.02-2.94) with four or more variants. Younger individuals with four or more variants were also at a significantly increased risk for lung cancer (OR, 3.15; 95% CI, 1.62-6.12). This study provides support for the multigenetic effects of variant alleles from p53 exon 4, and introns 3 and 6, and p73, and their interplay with smoking, resulting in a significantly increased risk for lung cancer in this Caucasian population.
(Cancer Epidemiol Biomarkers Prev 2006;15(1):158-61).