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Genetic analysis for carcinogen metabolism-related lung cancer risk among heavy smokers in the PLCO Trial SNP analysis

Principal Investigator
Name
Timothy Church
Degrees
-
Institution
University of Minnesota
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0009
Initial CDAS Request Approval
Jul 10, 2007
Title
Genetic analysis for carcinogen metabolism-related lung cancer risk among heavy smokers in the PLCO Trial SNP analysis
Summary
In the proposal, "Measuring carcinogen metabolite levels in long-term smokers and estimating the risk of lung cancer", approved by EEMS in 2006, the fourth specific aim of the study is:4. Genetic polymorphisms in three genes related to detoxification of tobacco [carcinogens].The approved proposal aims to use a case-control study to examine the relationship to lung cancer of biomarkers of exposure to and metabolic activation of tobacco carcinogens and to develop initial analyses of the relationship of genetic heterogeneity to both biomarkers and lung cancer risk. This addendum to that proposal identifies the single nucleotide polymorphisms (SNPs) of interest and outlines the rationale for the chosen genes.This addendum has been developed to extend the collaboration to a project at the University of Minnesota that includes faculty from the Department of Experimental and Clinical Pharmacology, the Department of Laboratory Medicine, the Department of Environmental Health Sciences, the Department of Biostatistics, and the Department of Genetics, Cell Biology & Development. From this diverse interest in clinical outcomes came a common platform for genetic studies, and the development by University of Minnesota personnel (in collaboration with Affymetrix), of a custom SNP Chip. The MN SNP Chip will simultaneously assess genetic variation in over 3,400 SNPs in 1000 genes that can affect disease risk and metabolic processes. In this proposal the goal will comprehensive analysis of functional SNPs and their association with lung cancer risk and biomarkers of metabolic activation of tobacco carcinogens in smokers. The particular SNPs of interest directly related to include: rs1056836 (CYP1B1L432V), rs1051740 (EPHX1Y113H), rs947894 (GSTP1I105V), and rs1799811 (GSTP1A114V), all 4 of which are related to tobacco carcinogen metabolism. However, by using a chip technology thousands of functional SNPs which are plausibly related to carcinogenesis can be assessed simultaneously at reasonable cost, allowing exploratory analysis of the relationship of heterogeneity in many other genes to lung cancer risk and biomarkers of exposure to and metabolic activation of tobacco carcinogens.
Aims

The main hypothesis of the parent study is that higher levels of carcinogen biomarkers in smokers will be associated with increased risk for lung cancer. The addendum is to determine whether, in a population of humans, single nucleotide polymorphisms (SNPs) in certain genes are associated with those biomarkers and with lung cancer diagnosis when combined with other known, measured risk factors for lung cancer, such as age, sex, and smoking history. Specifically, the additional proposes to. 1. Obtain from the study biorepository samples of lymphocytes or isolated DNA from the 200 participants in the parent study that are adequate to evaluate the approximately 3,400 SNPs in 100 genes using the MN SNP Chip, which includes the following SNPs: a. rs1056836 (CYP1B1L432V), b. rs1051740 (EPHX1Y113H), c. rs947894 (GSTP1I105V), d. rs1799811 (GSTP1A114V). 2. Combine with other PLCO study samples for the biomarkers and link the results to participant demographic data, smoking history, and lung cancer status to estimate the odds ratios of lung cancer and their simultaneous confidence regions for these SNPs, controlling for variables indicated by the presumed causal model, with appropriate sensitivity analyses. Since the frequency of these SNPs is low, the intent is to produce preliminary results to guide further research. 3. Assess in exploratory analyses SNPs in other genes, such as MGMT, MBD4, TDG, MUTYH, OGG1, APEX1, XRCC1, PARP1, POLD1, XPC, RAD23B, CCNH, LIG1, RAD51, XRCC3, RAD52, BRCA2, RAD50, LIG4, XRCC4, CYP1A2, CYP2A6, CYP2E1, GSTA1, TP53, PAX5, NRAS, KRAS, MYC, FAS, BCL2, BAX, MDM2, STAT6, NFKB1, VEGF, CCND1, CDK4, CDKN1A, and TIMP3.

Collaborators

Kristin Anderson (University of Minnesota)
Neil Caporaso (NCI, DCEG)
Stephen Hecht (University of Minnesota)
Timothy Church (University of Minnesota)
Brian VanNess (University of Minnesota)

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