Amos, Christopher I.

Abstract The rationale behind gene-disease association studies is that genetic variants (polymorphisms) result in alterations in intermediate phenotypes. However, genotype-phenotype correlations have not been established for most polymorphisms. In this study, we correlated genotype data of genes involved in the nucleotide excision repair pathway with mutagen sensitivity phenotype, quantified by benzo(a)pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocytes in 422 healthy subjects recruited into a twin study that included 138 pairs of monozygotic twins, 51 pairs of dizygotic twins, and 44 siblings. Among a panel of single nucleotide polymorphisms examined, we found that BPDE sensitivity was modified by individual polymorphisms in XPC, RAD23B, and XPA genes. Specific haplotypes and diplotypes of XPC also modified BPDE sensitivity profiles. In addition, a more consistent and stronger correlation was observed between mutagen sensitivity phenotype and the combination of multiple polymorphisms in the nucleotide excision repair pathway. Specifically, when XPC-PAT, XPC Lys939Gln, XPA A23G, and RAD23B Val249Ala were analyzed together, we observed a significant dose-response relationship between increasing mutagen sensitivity with increasing number of adverse alleles: mutagen sensitivity for those carrying zero to two, three to five, and six or more adverse alleles were 0.64, 0.68, and 1.06, respectively (P for trend = 0.008), and the results remained significant after adjusting for multiple comparisons. Using individuals carrying zero to two adverse alleles as the reference group, the risks of being mutagen sensitive (mutagen sensitivity values greater than the median) were 1.05 (95% confidence interval, 0.68-1.64) and 4.48 (95% confidence interval, 1.21-16.61) for those carrying three to five and six or more adverse alleles, respectively. Analyses of the effects of genotype combinations yielded similar results. These findings underscore the importance of assessing the collective effects of a panel of polymorphisms in the same pathway in modulating mutagen sensitivity. As risk assessment for cancer risk is moving toward a multigenic pathway-based approach, future genotype-phenotype correlation studies should also investigate the combined effects of multiple genetic variants. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2065–71)

Abstract Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, γ-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor. (Cancer Res 2006; 66(12): 5993-6)