The role of some chemicals and ionizing radiation in inducing DNA double-strand breaks that, if not repaired, are transformed into CAs during cell division is well established (Bryant 1998
; Natarajan 1993
; Obe et al. 2002
; Palitti 1998
; Savage 1998
). Measuring the frequency of chromosomal damage in humans exposed to occupational and environmental clastogens has been a priority in public health studies for decades, and an increased level of CAs in population groups is currently interpreted as evidence of genotoxic exposure and early biologic effects on DNA (Albertini et al. 2000
; Šrám 1981
; Šrám et al. 1983
; Waters et al. 1999
). However, before using CAs as a marker of cancer risk, it is essential to establish not only the presence of an association with exposure but also the link with cancer occurrence (WHO 2001
The results from this study contribute important evidence on CAs as a predictive cancer biomarker. One strength of these findings is the homogeneity of cytogenetic protocols in the laboratories included in the study, which should have reduced the misclassification due to technical variability. Furthermore, the size of this cohort, which is more than double the size of the combined Nordic–Italian cohorts (Hagmar et al. 1998
), allows the analysis of specific cancer sites, the study of interaction with occupational exposures, and the evaluation of subclasses of CAs.
The association between the total frequency of CAs and all cancer incidence was quantitatively lower than that reported in previous studies (Hagmar et al. 1998
), at least regarding the risk for those subjects in the highest tertile of the distribution of CA frequency. A possible explanation of this finding is the implementation of preventive interventions after the detection of a subject with a high CA level. In the Czech Republic, CA surveying was part of a systematic effort to provide an early detection of occupational damages, and subjects with a CA frequency of ≥4% were included in a program that was intended to reduce the risks for these individuals. An alternative explanation is that the association between CA frequency and cancer risk is weaker than previously considered.
Our results on the predictivity of CA subclasses support early data from Taiwan (Liou et al. 1999
) because a significant increase of incidence is described only for CSAs and not for CTAs. These findings are in agreement with the evidence that a double-strand break—which is a consolidated early event of carcino-genesis—is the primary lesion for CSAs, and that agents that produce double-strand breaks, such as ionizing radiation and radiomimetic clastogenic chemicals, create CSAs (Pfeiffer et al. 2000
). Such a difference was not detected in the combined analysis of the Nordic and Italian cohorts (Hagmar et al. 2004
The association between CA frequency and risk of specific cancers did not reveal a great variability, and positive associations might have been generated by multiple comparisons; however, the increase in cancers of digestive organs, and most notably stomach cancer, is a potentially important observation-that requires confirmation.
The presence of interaction between exposure to carcinogens and the predictivity of CAs has been another issue largely debated in the literature. The presence of a stronger association between CA frequency and risk of cancer in radon-exposed workers than in other workers or controls, which has been already reported (Smerhovsky et al. 2002
), is not consistent with the findings of the Nordic and Italian cohorts, in which the association between increased CA frequency and cancer risk appeared to be independent from exposure to carcinogens or smoking habit (Bonassi et al. 2000
). The findings from the present study were not conclusive in this direction because the predictivity of CA frequency observed in subjects exposed to various classes of carcinogens did not significantly differ from the group of nonexposed subjects. However, when the group of digestive cancers was cross-tabulated by occupational exposure, a significant association was seen only in the group of workers exposed to ionizing radiation. To better disentangle the interaction between radiation, CAs, and cancer, we further broke down CA subclasses in chromosome breaks and exchanges, and interestingly, the events mostly associated with digestive cancer incidence were exchanges, both chromatid exchanges (p
< 0.01) and chromosome exchanges (p
In conclusion, this study confirms previous reports of an association between the extent of chromosomal damage and the risk of cancer. In contrast to most previous reports, this association appeared to be limited to the presence of CSAs, and the magnitude of the excess risk might be lower than previously described. An original result of this analysis concerns the presence of a stronger association between CA frequency and cancers of the digestive tract. Also, the higher risks found in the group exposed to ionizing radiation is a peculiar finding of this cohort and deserves a deeper insight.
Furthermore, the possibility that the implementation of occupational preventive programs focused on workers with high CA frequency might have modified their risk of cancer is a plausible explanation of these results, and it will be further evaluated with ad hoc studies, reconstructing occupational lives of subjects with the highest frequency of CA at their first cytogenetic analysis.