Mutagen sensitivity is an in vitro short term lymphocyte culture assay that gauges host susceptibility by measuring induced chromatid breaks following exposure to an array of mutagens. A series of studies has indicated that mutagen sensitivity is a promising environmental-related cancer risk predictor. This assay has been expanded by replacing the initial test mutagen bleomycin with 4- nitroquinoline-1-oxide (4-NQO, a ultraviolet light (UV) mimetic agent), gamma-radiation, and benzo(alpha)pyrene diolepoxide (BPDE, a metabolic product of benzo(alpha)pyrene, which is a component of tobacco smoke) to measure risk of other cancers. However, all of the studies evaluating these assays have been done in unrelated individuals, and as a result, the extent to which mutagen sensitivity is likely to be an important cancer risk predictor, it is now apparent that the effect of genetics on mutagen sensitivity must be determined. One way of studying genetic influences is by comparing variance within monozygotic (MZ) versus dizygotic (DZ) twin pairs. In an effort to do this, we propose to conduct a study ancillary to a recently funded study in twins (R011DA11170) to test the hypothesis that mutagen-sensitive phenotypes are inherited. Following are the specific aims of the study proposed here: 1. Assess mutagen sensitivity using a panel of four mutagens (bleomycin, BPDE, 4-NQO, and gamma-radiation) in peripheral blood lymphocyte (PBL) cultures of 100 MZ and 100 DZ twin pairs. 2. Assess the measurement error in duplicate cultures, which will be done for 20 percent of the samples. While the assay has been shown to be reproducible and reliable, the measurement error for mutagen sensitivities has not been systematically evaluated. 3. Evaluate the infraclass correlations among these assays. Our hypothesis is that a person who is sensitive to one mutagen may be resistant to another because not all mutagens act through the same molecular mechanism. This may necessitate using a battery of mutagens to refine the ability to identify subpopulations at high risk of developing cancer. 4. Determine similarities and differences between twin pairs for each of the mutagen sensitivity assays, and use biometric genetic modeling to estimate the contribution of genetic influences to individual differences in these assays. Our hypothesis is that the similarity of these phenotypes will be greater in MZ twin pairs than in the DZ twin pairs because of an underlying heritable component. This research continues prior investigations on a panel of mutagen sensitivity biomarkers as predictors of cancer risk. Exploring the heritability of these susceptibility phenotypes will help elucidate the biologic response to mutagens. Additionally, these potential biomarkers may ultimately be used to identify individuals who should be targeted for more intense screening programs or behavior modification interventions.
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