Cytogenetic biomarkers and human cancer risk

Data on the role of the type of chromosomal aberrations (CAs) in cancer predictivity were obtained from Nordic, Italian, and Czech and other NAS cohorts. The findings suggested that both chromatid- and chromosome-type CAs are predictive of cancer risk, although chromosome-type CAs appeared to have a more important influence. Before the present project, information had been available on the role of CA type only from a small Taiwanese study. The present results are important in directing future research on the connection between CAs and cancer risk. They may suggest that emphasis should be aimed at studying the role of exposure to ionising radiation, a major source of chromosome-type CAs. The data from the Nordic-Italian and Czech studies have been published and presented in various scientific meetings. A manuscript has been prepared on the results of the other NAS cohorts. Sister chromatid exchanges (SCEs) were not indicative of cancer risk. The alternative use of high frequency SCE cells (HFCs) instead of mean number of SCEs per cell as the variable did not improve the cancer predicitivity of SCE analysis. A full-scale epidemiologic analysis of the cancer risk predictivity of SCEs with the supplemental information collected on technical features of the SCE test was not feasible. Thus, the results confirmed that the analysis of SCEs does not appear to have use in cancer prediction. The SCE assay can be used, e.g., in specific studies of occupational exposures to genotoxic carcinogens - where variation among culture batches and SCE analysis can be controlled between the exposed subjects and their referents. When data from various studies are combined for cancer risk prediction evaluation, the technical variation in SCE level is very difficult to manage. The classification of subjects in groups with high, medium, and low SCE counts thus becomes highly unreliable. The results on the cancer risk predictivity of SCEs and HFCs in the Italian cohort have been published. A manuscript is being prepared on the feasibility study.

Chromosomal aberrations (CAs) and micronuclei (MN) may be indicative of cancer risk because they reflect individual susceptibility factors. Inherited susceptibility to chromosome damage was assessed by genotype analysis using DNA extracted from fresh or frozen methanol-acetic acid fixed cell samples archived in the participating laboratories. The cell material available for the studies was derived from Belgium, Czech Republic, Finland, Hungary, and Norway. For the subjects, data on CAs, MN, or sister chromatid exchanges (SCEs) were available. Several polymorphisms of XMEs, DNA repair proteins, and enzymes of folate metabolism were able to affect the level of CAs and MN. For both CAs and MN, several polymorphisms seemed to interact with smoking and in some cases interaction with age was seen. Few polymorphisms appeared to have an impact on the frequency of SCEs. The complex findings probably reflect the multiple external and internal exposures inducing a multitude of DNA lesions eventually resulting in CAs and MN. Polymorphisms affecting the level of cytogenetic biomarkers can be viewed as potential factors influencing the cancer risk predictivity of CAs and MN. The magnitude of this tentative effect on cancer risk could not, however, be estimated, because genotype data were not available for most polymorphisms of interest in most cancer cases and controls of whom cytogenetic analyses were available. In the future, creation of a database combining genotype data and cytogenetic data from various European laboratories will make it possible to identify genotype combinations (or haplotypes) associated with exceptionally high rates of chromosome damage. The data collected in the present study will form an excellent starting point for such a database which is expected to be one step further towards the identification of genotypes that could markedly contribute to the association between chromosome damage and cancer risk. A number of scientific publications on the association of chromosome damage and genetic polymorphisms were published by the consortium during the project.

Studies on the cancer risk predictivity of chromosomal aberrations (CAs) concerned altogether 10 cohorts from four Nordic countries, Italy, Czech Republic, and 5 other countries who joined the project via NAS extension. The cohorts comprised altogether 21,832 subjects. The studies clearly showed that CA frequency is predictive of cancer. This predictivity was not due to undetected cancer, because it did not depend on the time elapsed from the CA analysis to the cancer detection. Both the Czech and the new NAS cohorts showed an association especially with stomach cancer. In the NAS cohort, a strong association also existed to colorectal cancer. The ongoing analysis of the pooled European cohort will shed more light on this matter. Thus, the results show that a positive chromosome aberration study, e.g., in occupational settings is an indication of increased cancer risk - besides exposure to genotoxic carcinogens. Confirmation of the cancer risk predictivity of chromosome damage can be utilised in development of strategies for cancer risk management and in risk assessment of genotoxic carcinogens by EU, WHO, and national regulatory bodies. The results will be useful for occupational physicians and toxicologists, radiation surveillance professionals, geneticists, and epidemiologists. The results will form a basis for planning a new collaborative project that should assess, e.g., (a) how the cancer risk predictivity of chromosome damage could be taken into account in regulation, (b) what are the prospects for individual risk assessment, and (c) what could explain the apparent preferential prediction of stomach cancer and colorectal cancer.

DNA could not successfully be extracted from old microscopic slides, but cell suspensions, available from Italy, Denmark, and Norway, could be genotyped for GSTM1 and GSTT1 polymorphisms. The effect of these two genotypes on cancer risk prediction by chromosomal aberrations (CAs) was then assessed. An association between CA level and cancer risk was obvious in all subcohorts, but statistically significant only in Italy. The Italian cohort showed a much stronger association between CAs and cancer risk than the two other cohorts, probably reflecting the fact that the Italian results were based on re-scored CA data, and therefore the intra-laboratory technical variability was removed. No significant effect could be demonstrated for GSTM1 or GSTT1 genotype, although the small risk associated with low-penetrant risk genotypes and the small numbers of the study probably explain the lack of significant results. Neither of the polymorphisms affected cancer risk prediction by CAs. The small numbers prevented further analyses involving specific tumour sites and genotype interaction with smoking and other exposures. The negative findings - despite the size of the study - seem to support the conclusion that the effect of CAs in predicting cancer is independent on single genotypes. However, general conclusions may not be drawn from the present result representing only two major polymorphisms of similar nature. GST polymorphisms, similar to other polymorphisms of xenobiotic metabolism, may be important especially in connection with specific exposures. If many polymorphisms affect CA level, the effect of a single polymorphism on the cancer predictivity of CAs can be expected to be low. The results were reported in the Final Report and are being prepared for publication.

The studies of MN and cancer predictivity revealed a clear association between the frequency of MN and subsequent risk of cancer. The extent of risks observed was close to that measured for CAs. Thus, MN analysis, which is easier, cheaper, and faster than CA scoring, may provide an alternative for CAs in cancer risk prediction. The issue of specific tumour sites is still open for MN, given the short follow-up of most cohorts and the consequent small number of cancer cases. An association of MN frequency with cancer risk has not been shown before. The earlier studies had given negative results, but were also based on methodologically more heterogeneous data and smaller cohorts. When the present cohorts will become older and more cases will be accumulated, further follow-ups will provide more information on, e.g., specific cancer sites. Expansion to new cohorts will also be possible. The results will be utilized by the scientific community, representing experts, e.g., in cytogeneticists, human genetics, epidemiology, occupational health, and cancer research. Users also include laboratories performing cytogenetic monitoring of subject occupationally exposed to known or suspected carcinogens (chemicals and radiation), occupational health care units, and risk assessment bodies. The association between MN frequency and cancer risk is expected to promote the use of the MN assay as a biomarker of cancer risk in surveillance of occupational groups exposed to known or suspected carcinogens.

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