Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk
Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk
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DOI：
10.1158/0008-5472.can-06-0326
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Spitz, Margaret R.
中科院分区：
文献类型：
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作者：
El-Zein, Randa A.;Schabath, Matthew B.;Spitz, Margaret R.
在这项病例对照研究中，我们修改了微核阻断试验（CBMN），这是一种已建立的基因组不稳定性生物标志物，通过测量每1,000个双核淋巴细胞中NNK诱导的染色体损伤终点（微核、核质桥和核芽）的频率，评价对尼古丁衍生亚硝胺4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）的敏感性。与对照组相比，肺癌患者的自发性和NNK诱导的染色体损伤显著更高。47%的病例（对照组为12%）有≥ 4个自发微核，66%的病例（无对照组）有4个自发核质桥，25%的病例（对照组为5%）有≥ 1个自发核芽（Ti < 0.001）。同样，40%的病例（对照组为6%）有5个NNK诱导的微核，89%的病例（无对照组）有≥ 6个诱导的核质桥，23%的病例（对照组为2%）有≥ 2个诱导的核芽（P < 0.001）。当在连续尺度上分析时，自发微核、核质桥和核芽分别与癌症风险增加2倍、29倍和6倍相关。同样，NNK诱导的风险分别为2.3、45.5和10倍。我们评估了CBMN测定法在预测癌症风险方面的应用，该方法基于微核、核质桥和核芽的数量（由对照组中的百分位数临界点定义）。当使用自发和NNK诱导的微粒体、核质桥和核芽的第95次扫描时，成为癌症患者的概率分别为96%、98%和100%。我们的研究表明，CBMN检测对NNK诱导的遗传损伤非常敏感，可以作为肺癌风险的强有力预测指标。
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 >= 4 spontaneous micronuclei, 66% of cases (and no controls) had 4 spontaneous nucleoplasmic bridges, and 25% of cases (versus 5% of controls) had >= 1 spontaneous nuclear bud (Ti < 0.001). Similarly, 40% of cases (versus 6% of the controls) had 5 NNK-induced micronuclei, 89% of cases (and no controls) had >= 6 induced nucleoplasmic bridges, and 23% of cases (versus 2% of controls) had >= 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 micromiclei, 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.