Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk

Cancer Res. 2006 Jun 15;66(12):6449-56. doi: 10.1158/0008-5472.CAN-06-0326.

Abstract

In this case-control study, we modified the cytokinesis-block micronucleus (CBMN) assay, an established biomarker for genomic instability, to evaluate susceptibility to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring the frequency of NNK-induced chromosomal damage endpoints (micronuclei, nucleoplasmic bridges, and nuclear buds) per 1,000 binucleated lymphocytes. Spontaneous and NNK-induced chromosomal damage were significantly higher in lung cancer patients compared with controls. Forty-seven percent of cases (versus 12% of controls) had >or=4 spontaneous micronuclei, 66% of cases (and no controls) had >or=4 spontaneous nucleoplasmic bridges, and 25% of cases (versus 5% of controls) had >or=1 spontaneous nuclear bud (P < 0.001). Similarly, 40% of cases (versus 6% of the controls) had >or=5 NNK-induced micronuclei, 89% of cases (and no controls) had >or=6 induced nucleoplasmic bridges, and 23% of cases (versus 2% of controls) had >or=2 induced nuclear buds (P < 0.001). When analyzed on a continuous scale, spontaneous micronuclei, nucleoplasmic bridges, and nuclear buds were associated with 2-, 29-, and 6-fold increases in cancer risk, respectively. Similarly, NNK-induced risks were 2.3-, 45.5-, and 10-fold, respectively. We evaluated the use of CBMN assay to predict cancer risk based on the numbers of micronuclei, nucleoplasmic bridges, and nuclear buds defined by percentile cut points in controls. Probabilities of being a cancer patient were 96%, 98%, and 100% when using the 95th percentiles of spontaneous and NNK-induced micronuclei, nucleoplasmic bridges, and nuclear buds, respectively. Our study indicates that the CBMN assay is extremely sensitive to NNK-induced genetic damage and may serve as a strong predictor of lung cancer risk.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogens
  • Case-Control Studies
  • Cytokinesis / genetics
  • DNA Repair
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / genetics*
  • Male
  • Micronuclei, Chromosome-Defective / chemically induced
  • Micronucleus Tests
  • Middle Aged
  • Nitrosamines

Substances

  • Carcinogens
  • Nitrosamines
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone