Use of the Cytokinesis-Blocked Micronucleus Assay to Detect Gender Differences and Genetic Instability in a Lung Cancer Case–Control Study

McHugh, Michelle K.; Lopez, Mirtha S.; Ho, Chung‐Han; Spitz, Margaret R.; Etzel, Carol J.; El‐Zein, Randa

doi:10.1158/1055-9965.epi-12-0435

Cited by 19 publications

(15 citation statements)

References 90 publications

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“…We have previously reported in a pilot study and confirmed in a larger study (18–20) that BN-MN and BN-NPB are strong predictors of lung cancer susceptibility with an overall positive predictive value of 96.1 and negative predictive value of 89.7 associated with disease status (19). In the current study, we externally validate our findings in an independent lung cancer population and test the effect of extending an existing lung cancer risk prediction model (21) with the CBMN endpoints.…”

Section: Introductionsupporting

confidence: 57%

The Cytokinesis-Blocked Micronucleus Assay as a Strong Predictor of Lung Cancer: Extension of a Lung Cancer Risk Prediction Model

El‐Zein

Lopez

D’Amelio

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background There is an urgent need to improve lung cancer outcome by identifying and validating markers of risk. We previously reported that the cytokinesis-blocked micronucleus assay (CBMN) is a strong predictor of lung cancer risk. Here we validate our findings in an independent external lung cancer population and test discriminatory power improvement of the Spitz risk prediction model upon extension with this biomarker. Methods 1,506 participants were stratified into a test set of 995 (527 cases /468 controls) from MD Anderson Cancer Center and a validation set of 511 (239 cases / 272 controls) from Massachusetts General Hospital. An epidemiologic questionnaire was administered and genetic instability was assessed using the CBMN assay. Results Excellent concordance was observed between the two populations in levels and distribution of CBMN endpoints [binucleated-micronuclei (BN-MN), binucleated-nucleoplasmic bridges (BN-NPB)] with significantly higher mean BN-MN and BN-NPB values among cases (P<0.0001). Extension of the Spitz model led to an overall improvement in the AUC (95% CI) from 0.61 (55.5 – 65.7) with epidemiological variables to 0.92 (89.4 – 94.2) with the addition of BN-MN endpoint. The most dramatic improvement was observed with the never smokers extended model followed by the former and current smokers. Conclusions The CBMN assay is a sensitive and specific predictor of lung cancer risk and extension of the Spitz risk prediction model led to an AUC that may prove useful in population screening programs to identify the “true” high risk individuals. Impact Identifying high-risk subgroups that would benefit from screening surveillance has immense public health significance.

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Section: Introductionsupporting

confidence: 57%

The Cytokinesis-Blocked Micronucleus Assay as a Strong Predictor of Lung Cancer: Extension of a Lung Cancer Risk Prediction Model

El‐Zein

Lopez

D’Amelio

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In our study, we demonstrate that although both SCLC and NSCLC cases had significantly higher levels of genetic instability (BN-MN, BN-NPB, and BNBUDs) as compared to healthy cancer-free controls, only the levels of the BN-NPBs were significantly higher among the SCLC cases as compared to the NSCLC cases ( p < 0.001). While we have previously reported that the multi-endpoint CBMN assay is a sensitive predictor of lung cancer risk [McHugh et al, 2013], to our knowledge, this is the first study to compare the level of genetic instability between SCLC and NSCLC cases using this multiendpoint approach.…”

Section: Discussionmentioning

confidence: 99%

“…BN-BUDs represent a mechanism by which cells remove amplified DNA and are therefore considered a marker of possible gene amplification through a breakage-fusion-bridge cycle [Fenech, 2002a]. We have previously reported that the CBMN DNA damage endpoints are strong predictors of NSCLC susceptibility [El-Zein et al, 2006McHugh et al, 2013] with a positive predictive value of 91% among smokers.…”

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confidence: 99%

Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays

El‐Zein

Abdel-Rahman

Santee

et al. 2017

Cytogenet Genome Res

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Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. There is an urgent need to develop tools to identify individuals at high risk of developing SCLC. We have previously reported that the cytokinesis-blocked micronucleus (CBMN) assay is a strong predictor of non-small cell lung cancer (NSCLC). Here, we investigate the sensitivity of the CBMN endpoints as predictors of SCLC risk. We conducted the CBMN assay on SCLC patients (n = 216), NSCLC patients (n = 173), and healthy controls (n = 204). Per sample, 1,000 binucleated cells (BN) were scored, and 3 endpoints, micronuclei (BN-MN), nucleoplasmic bridges (BN-NPB), and nuclear buds(BN-BUD), were recorded. Spectral karyotyping was also conducted on SCLC patients (n = 116) and NSCLC patients (n = 137) to identify genomic regions unique to each disease. Significantly higher levels of CBMN endpoints were observed in both cancer groups compared to controls. BN-NPBs were significantly higher among SCLC patients compared to NSCLC patients (p < 0.001). Chromosomes 5 and 17 were associated with BN-MN, and chromosomes 5, 18, 20, and 22 were associated with BN-NPBs in SCLC patients. Given the high frequency of chromosome aberrations observed in SCLC, events such as reinsertion of the micronucleus and chromothripsis may be potential mechanisms for the genetic instability in these patients.

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“…MN, NPBs, and NBUDs are nuclear alterations characteristic of chromosomally unstable cells often detected in tumor cells and peripheral blood of patients with cancer [41]. The frequency of nuclear alterations observed by CBMN is a relevant biomarker for the risk of lung cancer and melanoma, and can be used for early detection of the disease, making it a useful tool in clinical and epidemiological studies [42,43]. The CBMN method also allows assessment of the impact of micronutrients in the diet and the combination of micronutrients on DNA damage, revealing the carcinogenic or protective potential of certain diets [44,45].…”

Section: Introductionmentioning

confidence: 99%

Cytokinesis-Block Micronucleus Assay Adapted for Analyzing Genomic Instability of Human Mesenchymal Stem Cells

Cornélio

Tavares

Pimentel

et al. 2014

Stem Cells and Development

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Human mesenchymal stem cells (hMSCs) are multipotent cells used in cell therapy research. One of the problems involving hMSCs is the possibility of genetic instability during in vitro expansion required to obtain a suitable number of cells for clinical applications. The cytokinesis-block micronucleus (CBMN) assay measures genetic instability by analyzing the presence of micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) in binucleated cells. The present study describes modifications in the CBMN assay methodology to analyze genetic instability in hMSCs isolated from the umbilical vein and in vitro expanded. The best protocol to achieve binucleated hMSCs with preserved cytoplasm was as follows: cytochalasin B concentration (4.0 μg/mL), use of hypotonic treatment (3 min), and the fixative solution (9 methanol:1 acetic acid). These adaptations were reproduced in three hMSC primary cell cultures and also in XP4PA and A549 cell lines. The frequency of hMSCs treated with mitomycin-C presenting MN was lower than that with other nuclear alterations, indicating that the hMSCs contain mechanisms to avoid a high level of chromosomal breaks. However, a high frequency of cells with NPBs was detected and spontaneous anaphase bridges under normal hMSC in vitro culture were observed. Considering that anaphase bridges are characteristic alterations in tumor cells, the CBMN assay is indicated as an important tool associated with other genetic analyses in order to ensure the safe clinical use of hMSCs in cell therapy.

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Use of the Cytokinesis-Blocked Micronucleus Assay to Detect Gender Differences and Genetic Instability in a Lung Cancer Case–Control Study

Cited by 19 publications

References 90 publications

The Cytokinesis-Blocked Micronucleus Assay as a Strong Predictor of Lung Cancer: Extension of a Lung Cancer Risk Prediction Model

The Cytokinesis-Blocked Micronucleus Assay as a Strong Predictor of Lung Cancer: Extension of a Lung Cancer Risk Prediction Model

Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays

Cytokinesis-Block Micronucleus Assay Adapted for Analyzing Genomic Instability of Human Mesenchymal Stem Cells

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