Cytokinesis-Blocked Micronucleus Cytome Assay Biomarkers Identify Lung Cancer Cases Amongst Smokers

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 17; no. 5; pp. 1111 - 1119
• Main Authors: El-Zein, Randa A, Fenech, Michael, Lopez, Mirtha S, Spitz, Margaret R, Etzel, Carol J
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-05-2008
• Subjects: Apoptosis; Biomarkers, Tumor - genetics; Case-Control Studies; Chi-Square Distribution; Chromosome Aberrations; cytogenetics; Cytokinesis - genetics; DNA Damage; Female; Genetic Predisposition to Disease; Humans; Logistic Models; lung cancer risk; Lung Neoplasms - genetics; Male; Micronuclei, Chromosome-Defective; Micronucleus Tests; Middle Aged; Nitrosamines; NNK; Risk Factors; Smoking - adverse effects; Surveys and Questionnaires
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.EPI-07-2827

The multi-endpoint cytokinesis-blocked micronucleus assay is used for assessing chromosome aberrations. We have recently reported
that this assay is extremely sensitive to genetic damage caused by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) and that the binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds in lymphocytes (chromosome
damage endpoints measured by the assay) are strong predictors of lung cancer risk. In the current study, we refined our analysis
to include toxicity endpoints (micronuclei in mononucleated cells, apoptosis, necrosis, and nuclear division index) to investigate
the benefit of including these variables on improving the predictive value of the assay. Baseline and NNK-induced micronuclei
in mononucleated cells were significantly higher in patients ( n = 139) than controls ( n = 130; P < 0.001). Baseline apoptosis was higher among cases; however, the controls showed a significant higher fold increase in NNK-induced
apoptosis compared with baseline ( P < 0.001). Principal components analysis was used to derive a summary measure for all endpoints and calculate the positive
predictive value (PPV) and negative predictive value (NPV) for disease status. First principal component for NNK-induced chromosome
damage endpoints (binucleated cells with micronuclei, nucleoplasmic bridges, and nuclear buds) had an area under the curve
= 97.9 (95% confidence interval, 95.9-99.0), PPV = 94.8, and NPV = 92.6. The discriminatory power improved when micronuclei
in mononucleated cells were included: area under the curve = 99.1 (95% confidence interval, 97.9-100.0), PPV = 98.7 and NPV
= 95.6. The simplicity, rapidity, and sensitivity of the assay together with potential for automation make it a valuable tool
for screening and prioritizing potential cases for intensive screening. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1111–9)