The usefulness of cytogenetic biomarkers as intermediate endpoints in carcinogenesis

Abstract

During the last decades, cytogenetic biomarkers in peripheral lymphocytes have been used to assess exposure to carcinogenic or mutagenic agents in occupational settings. The first method in use assessed chromosomal aberrations (CA). It is generally accepted that chromosomal mutations are causal events in the development of neoplasia, and it has earlier been postulated, but not proven, that increased chromosomal damage may reflect an enhanced cancer risk. Two less laborious techniques, sister chromatoid exchanges (SCE) and micronuclei (MN), were introduced later-on in occupational health surveillances. SCE represent symmetrical exchanges between sister chromatids; generally they do not result in alteration of the chromosome morphology. MN represent small, additional nuclei formed by the exclusion of chromosome fragments or whole chromosomes lagging at mitosis. MN rates therefore indirectly reflect chromosome breakage or impairment of the mitotic apparatus. The health significance of increased levels of SCE and MN is poorly understood. The usefulness of these cytogenetic techniques for implementing preventive measures in the workplaces depend on how well they serve as biomarkers of exposure but also on whether they can predict cancer risk or not. Recently performed epidemiological studies show that the CA frequency predicts the overall cancer risk in healthy subjects. Such associations could not been seen for SCE or MN. Age, sex, or time since test did not affect the predictive value of CA. This predictivity was seen irrespective of whether the subjects had been smokers or occupationally exposed to carcinogenic agents. Risk factors such as age, smoking and occupational exposures usually explain only some of the interindividual variation in CA frequency. It seems reasonable that not yet identified individual susceptibility factors explain a large fraction of the interindividual CA variation and also the cancer predictivity of the CA biomarker.