The frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) is extensively used as a biomarker of chromosomal damage and genome stability in human populations. Much theoretical evidence has been accumulated supporting the causal role of MN induction in cancer development, although prospective cohort studies are needed to validate MN as a cancer risk biomarker. A total of 6718 subjects from of 10 countries, screened in 20 laboratories for MN frequency between 1980 and 2002 in ad hoc studies or routine cytogenetic surveillance, were selected from the database of the HUman MicroNucleus (HUMN) international collaborative project and followed up for cancer incidence or mortality. To standardize for the inter-laboratory variability subjects were classified according to the percentiles of MN distribution within each laboratory as low, medium or high frequency. A significant increase of all cancers incidence was found for subjects in the groups with medium (RR=1.84; 95% CI: 1.28-2.66) and high MN frequency (RR=1.53; 1.04-2.25). The same groups also showed a decreased cancer-free survival, i.e. P=0.001 and P=0.025, respectively. This association was present in all national cohorts and for all major cancer sites, especially urogenital (RR=2.80; 1.17-6.73) and gastro-intestinal cancers (RR=1.74; 1.01-4.71). The results from the present study provide preliminary evidence that MN frequency in PBL is a predictive biomarker of cancer risk within a population of healthy subjects. The current wide-spread use of the MN assay provides a valuable opportunity to apply this assay in the planning and validation of cancer surveillance and prevention programs.

Over a century ago, Theodor Boveri paved the way to mechanistic studies linking chromosomal abnormalities to cancer pathogenesis. Since then, theoretical and empirical evidence has been accumulated, supporting a causal role of these events in the aetiology of human cancer. A powerful tool for measurement of chromosomal abnormalities is the cytokinesis-block micronucleus cytome (CBMNcyt) assay. The validation of the micronucleus (MN) as marker of phenotypic susceptibility to cancer has received decisive support from mutagens sensitivity studies, particularly from a recent case–control study on lung cancer, which showed increased frequency of tobacco carcinogen-induced MN, nuclear buds and especially nucleoplasmic bridges in cancer patients (odds ratios of 2.3, 10.0 and 45.5, respectively). Recently, a large international cohort study showed a significant association between MN frequency in healthy subjects and cancer risk. The study assembled data on 6718 individuals from 10 countries (62 980 person-years). Cancers incidence was significantly higher in groups with medium (RR = 1.84; 95% confidence interval: 1.28–2.66) and high MN frequency (RR = 1.53; 95% CI: 1.04–2.25). This study provided preliminary evidence that MN frequency in peripheral blood lymphocytes is predictive of cancer risk, suggesting that increased MN formation is associated with early events in carcinogenesis. These results, in combination with mechanistic evidence, prospected the use of MN frequency in cancer screening programmes. However, issues such as interindividual variability and preventive strategies in high-risk groups need to be further addressed to consolidate these achievements.