This application builds upon the case-control recruitment and specimen recourses of an ongoing funded molecular epidemiology lung cancer study in the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center (CA55769, M. R. Spitz, PI). The goal of the current application is to validate and extend our compelling preliminary data the Cytokinesis-block micronucleus (CBMN) assay [a cytogenetic biomarker measuring DNA damage] in human lymphocytes as a biomarker for identification of individuals at risk of lung cancer. In a pilot study of, we demonstrated the high sensitivity of the assay as biomarker of risk of lung cancer using the tobacco-specific nitrosamine NNK as a challenge mutagen. In the current application, we propose to confirm our findings in a larger case control setting of 250 cases and 250 controls, and to explore the possibility of identifying the specific chromosomes involved in the NNK-induced damage. We will test the hypothesis that NNK-induced CBMN assay is a sensitive predictor of lung cancer risk due to involvement of specific regions in the genome that are critical for lung carcinogenesis. We propose the following aims: 1) To confirm our initial observation indicating that the CBMN assay is a sensitive marker for identifying individuals at risk of developing lung cancer. Both spontaneous and NNK- induced chromosome damage will be measured in an additional 250 cases and 250 controls. 2.a) To determine the specific chromosome regions involved in the production of the observed aberrations in both spontaneous and NNK-induced cytogenetic cultures using FISH probes (pancentromeric, telomeric and SKY probes). 2.b) In a subset of patients, we will then determine the specificity of these aberrations using molecular cytogenetics, in lung tissues. Confirmation that surrogate markers are representative of molecular changes in the target tissue has implications for population-based molecular epidemiologic research that uses surrogate tissues to evaluate genetic susceptibility to cancer. The overall goal of this application is to allow the development of this robust assay into a cancer risk assessment tool for identification of high-risk individuals. In the current study we propose to test the use of the tobacco-specific nitrosamine induced Cytokinesis-block micronucleus assay as a novel marker for lung cancer risk assessment. We will first validate our initial findings demonstrating the high sensitivity of this assay as a predictor of lung cancer risk. We will then explore the possibility of identifying the specific chromosome regions involved in the chromosome lesions observed in peripheral blood and in target tissues. This approach will in turn allow the development of this assay into a cancer risk assessment tool for identification of high-risk individuals.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Epidemiology of Cancer Study Section (EPIC)
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Divi, Rao L
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University of Texas MD Anderson Cancer Center
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United States
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El-Zein, Randa A; Etzel, Carol J; Munden, Reginald F (2018) The cytokinesis-blocked micronucleus assay as a novel biomarker for selection of lung cancer screening participants. Transl Lung Cancer Res 7:336-346
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El-Zein, Randa A; Lopez, Mirtha S; D'Amelio Jr, Anthony M et al. (2014) The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model. Cancer Epidemiol Biomarkers Prev 23:2462-70
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Lloyd, Stacy M; Lopez, Mirtha; El-Zein, Randa (2013) Cytokinesis-blocked micronucleus cytome assay and spectral karyotyping as methods for identifying chromosome damage in a lung cancer case-control population. Genes Chromosomes Cancer 52:694-707
Monroy, Claudia M; Cortes, Andrea C; Lopez, Mirtha et al. (2011) Hodgkin lymphoma risk: role of genetic polymorphisms and gene-gene interactions in DNA repair pathways. Mol Carcinog 50:825-34
Rondelli, Catherine M; El-Zein, Randa A; Wickliffe, Jeffrey K et al. (2010) A comprehensive haplotype analysis of the XPC genomic sequence reveals a cluster of genetic variants associated with sensitivity to tobacco-smoke mutagens. Toxicol Sci 115:41-50
Katz, Ruth L; He, Weigong; Khanna, Abha et al. (2010) Genetically abnormal circulating cells in lung cancer patients: an antigen-independent fluorescence in situ hybridization-based case-control study. Clin Cancer Res 16:3976-87
El-Zein, Randa A; Monroy, Claudia M; Cortes, Andrea et al. (2010) Rapid method for determination of DNA repair capacity in human peripheral blood lymphocytes amongst smokers. BMC Cancer 10:439