Chromosomal Aberrations in Lymphocytes
There is evidence that increased frequency of chromosomal aberration (CA) in peripheral blood lymphocytes is a predictor of cancer, but further data are needed to better characterize CA as marker of cancer risk. From the archives of 15 laboratories we gathered cytogenetic records of 11,834 subjects who were free of cancer at the moment of blood drawing and who underwent cytogenetic examination for preventive purposes in the Czech Republic during 1975-2000. We linked these records to the national cancer registry, revealing a total of 485 cancer cases. Subjects were classified according to the percentiles of CA distribution within each laboratory as low (0-33rd percentile), medium (34-66th percentile), and high (66-100th percentile). Subjects were further classified by occupational exposure and by subclass of CA. We found a significant association between the overall cancer incidence and the presence of chromosome-type aberrations [relative risk (RR) for high vs. low CA level = 1.24; 95% confidence interval (CI), 1.03-1.50] but not chromatid-type aberrations. Stomach cancer showed a strong association with frequency of total CA (RR = 7.79; 95% CI, 1.01-60.0). The predictivity of CA observed in subjects exposed to various classes of carcinogens did not significantly differ from the group of nonexposed subjects. This study contributes to validation of CA as a predictive marker of cancer risk, in particular, of stomach cancer; the association between CA frequency and cancer risk might be limited to chromosome-type aberrations.

The frequency of chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBLs) measured with the conventional cytogenetic assay in metaphase cells has routinely been used for several decades as a tool to monitor occupational and environmental exposures to genotoxic carcinogens. There is ample evidence of the value of this biomarker for the identification of occupational and environmental hazards (Albertini et al. 2000; Bonassi et al. 2005; Carrano and Natarajan 1988; Rossner et al. 1995; Srám and Binkova 2000; Waters et al. 1999). However, the concept of chromosomal damage as a biomarker of early carcinogenic effects rests on the evidence of an association between biomarker frequency and cancer risk, in addition to that of an association between biomarker and exposure to genotoxic agents.

The hypothesis of a positive association between the frequency of CAs in PBLs and the risk of cancer at different sites has been supported--besides theoretical considerations (Cheng and Loeb 1993; Mitelman 2000; Sorsa et al. 1992; Yunis 1983)--by numerous clinical observations, in particular, of patients suffering from hereditary chromosome breakage syndromes (Mathur et al. 2000) and several other precancerous conditions such as preleukemic states of adult T-cell leukemia (Nishino 1988), dysplastic nevus syndrome (Caporaso et al. 1987), or nevoid basal-cell syndrome (Shafei-Benaissa et al. 1998). Case-series and case-control studies have reported a significant increase in the frequency of aberrant cells in untreated cancer patients (Abarbanel et al. 1991; Barrios et al. 1988, 1991; Dave et al. 1995; Dhillon and Dhillon 1998; Dhillon et al. 1996; Gebhart et al. 1993; Trivedi et al. 1998), but these studies have been subject to criticism because of small sample sizes and not accounting for the inherent reverse causality bias, that is, when the biomarker may be affected by the disease.

More conclusive evidence on the association between CA and cancer comes from prospective cohort studies (Bonassi et al. 2004). An increased risk of cancer incidence was observed in individuals classified as having high CA frequency in a Nordic cohort (Hagmar et al. 1994, 1998), in an Italian cohort (Bonassi et al. 1995), and, limited to chromosome-type aberrations (CSAs) in a nested case-control study carried out in Taiwan (Liou et al. 1999). In a case-control study nested within the joint Nordic and Italian cohorts, the association between CA frequency and risk of cancer was not modified by sex, age, cigarette smoking, occupational exposure, or time since the cytogenetic assay (Bonassi et al. 2000).

In the Czech Republic, the evaluation of CA frequency in PBLs has been included since 1975 in regular medical checkups of workers exposed to selected occupational hazards, making it feasible to identify a cohort of individuals for prospective follow-up for cancer in order to confirm the results of the studies from Nordic countries, Italy, and Taiwan. The large number of individuals with CA measurements and the detailed cytogenetic records allowed us to test the hypothesis that specific cytogenetic end points may be linked to the incidence of cancer at specific anatomical sites, thus expanding our preliminary results, in particular, those concerning a group of miners exposed to radon (Smerhovsky et al. 2001, 2002).