Review
Micronuclei frequency in peripheral blood lymphocytes of cancer patients: A meta-analysis

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Abstract

Micronuclei (MN) frequency is a biomarker of chromosomal damage, genome instability, and cancer risk that integrates acquired mutations and genetic susceptibility. To evaluate and summarize the evidence reporting association between cancer and MN formation, we performed a meta-analysis assessing the frequency of this biomarker in cancer patients. Findings from 37 publications were retrieved through an extensive search of the MedLine/PubMed database. Given the heterogeneity of the study design, all studies were re-classified into three groups: (i) baseline MN frequency of untreated cancer patients (25 studies), (ii) induced MN frequency in thyroid cancer patients undergoing radioiodine treatment (9 studies), and (iii) radiosensitivity of lymphocytes (12 studies) in untreated cancer patients. A meta-estimate of the frequency ratio (meta-FR) was computed in each group. A significant increase of MN frequency was found in untreated cancer patients (meta-FR = 1.45; 95% Confidence Interval (95% CI): 1.28–1.64) and in thyroid cancer patients after radioiodine treatment (meta-FR = 2.26; 95% CI: 1.90–2.68). The third meta-analysis showed a negative trend of meta-FR's when plotted vs. the dose used to study patients’ radiosensitivity, possibly associated to a high rate of apoptosis. The results of this review substantiate the existing evidence about a role of MN in various steps of carcinogenesis. The relatively small numbers of papers suitable for the meta-analysis call for new and larger studies, possibly based on high-throughput techniques, to further understand the role of MN formation in the occurrence of genetic instability and cancer.

Introduction

Changes in chromosome structure and number, as well as genomic instability, are major events in the etiological pathway leading to cancer [1], [2]. The use of biomarkers associated with these events may provide useful tools for the early detection of disease-related changes [3]. Markers of chromosome damage such as the frequency of chromosomal aberrations (CA) and micronuclei (MN) are among the most frequently used biomarkers for this purpose [4], [5], [6], [7]. The similarity between the level of chromosome damage in surrogate tissues, such as oral mucosa or peripheral blood lymphocytes (PBL), and the corresponding damage in cancer-prone tissues provide the rationale for the use of these biomarkers as markers of cancer risk [8]. In particular, the high reliability and low cost of the micronucleus assay has contributed to the worldwide success and adoption of this biomarker for in vitro and in vivo studies of genome damage [5]. Indeed, the MN assay has in fact evolved into a “cytome” method for comprehensively measuring chromosome-instability phenotypes and altered cellular viabilities [9]. Micronuclei can be generated through different processes, i.e., chromosome breakage and chromosome loss (aneuploidy) [10], [11], [12] (Fig. 1).

The hypothesis of an association between MN frequency and cancer development is supported by a number of observations. The most substantiated include: (i) the high frequency of this biomarker in untreated cancer patients and in subjects affected by cancer-prone congenital diseases, (ii) the correlation existing between genotoxic MN-inducing agents and carcinogenicity, and (ii) the inverse correlation between MN frequency and the blood concentration and/or dietary intake of certain micronutrients associated with reduced cancer risk [11]. Further evidence comes from the results of recent cohort studies, which in most cases demonstrated that the frequency of CA [8], [13] (given the mechanistic and experimental correlation existing between CA and MN) or MN [11], [14] in PBL of healthy subjects is a predictor of cancer risk. However, despite this extensive evidence, it is difficult to establish a causal relationship between MN frequency and cancer risk because a high MN level in cancer patients could be a consequence of their disease status, i.e., reverse causality, or reflect their individual susceptibility to genomic instability events [14].

The present article aims at evaluating and summarizing the available evidence linking cancer status to MN formation in PBL. The use of the meta-analysis seems the most informative way to extract information from studies on biomarkers when the evidence from single studies is too sparse to support definite conclusions [5], [15]. However, given the heterogeneity of human studies available in the scientific literature, we decided to perform separate meta-analyses, not only to compare MN frequency in untreated cancer patients vs. referent donors, but also to identify the extent of individual susceptibility in cancer patients undergoing radio-therapeutic treatment.

Section snippets

Search strategy

The main purpose of this study was to summarize the evidence published in the literature concerning the association between MN frequency in PBL and the presence of a diagnosis of cancer. To avoid the effect of chemo or radiotherapy, studies on untreated patients were preferentially selected.

We performed an extensive literature search without any language restriction by using the MedLine/PubMed database (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA-//www.ncbi.nlm.nih.gov/PubMed

Results

The main characteristics of original datasets are shown in Table 3, Table 4, Table 5. For each study, we reported selected design features (cancer type, size of the study groups, percentage of males and mean age), main findings (mean MN frequency ± standard error (S.E.) in 1000 binucleated cells), the patient/referent FRs, and the first author and the year of publication. We evaluated the potential confounding effect of selected covariates, i.e., mean age and the percentages of males and smokers

Discussion

The main purpose of this study is to evaluate and summarize the available evidence linking cancer status to MN formation in PBL. The frequency of this biomarker in surrogate tissues as a marker of cancer risk and progression is a topic attracting increasing interest for its potential applications to clinical oncology and public health, as confirmed by the dramatically increasing trend of published papers. The heterogeneity of studies retrieved from the MedLine forced us to extend our interests

Conclusion

The results of this review substantiate the existing evidence about a role of MN in various steps of carcinogenesis and clearly show that the level of baseline chromosome damage in untreated cancer patients is much higher than in cancer-free referents. Indeed, MN are generally used as a biomarker of chromosomal damage, genome instability, and cancer risk, integrating acquired mutations and genetic susceptibility. Several factors could explain cancer predictivity of MN, e.g., environmental

Acknowledgements

We thank Donatella Ugolini (National Cancer Research Institute, Genoa, Italy) for her help in search of the MedLine/PubMed database. This study was supported by grants funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Italian Space Agency and by the Fondazione ONLUS-Buzzi.

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