Mechanistic evidence linking chromosomal aberration (CA) to early stages of cancer has been recently supported by the results of epidemiological studies that associated CA frequency in peripheral lymphocytes of healthy individuals to future cancer incidence. To overcome the limitations of single studies and to evaluate the strength of this association, a pooled analysis was carried out. The pooled database included 11 national cohorts and a total of 22 358 cancer-free individuals who underwent genetic screening with CA for biomonitoring purposes during 1965–2002 and were followed up for cancer incidence and/or mortality for an average of 10.1 years; 368 cancer deaths and 675 incident cancer cases were observed. Subjects were classified within each laboratory according to tertiles of CA frequency. The relative risk (RR) of cancer was increased for subjects in the medium [RR = 1.31, 95% confidence interval (CI) = 1.07–1.60] and in the high (RR = 1.41; 95% CI = 1.16–1.72) tertiles when compared with the low tertile. This increase was mostly driven by chromosome-type aberrations. The presence of ring chromosomes increased the RR to 2.22 (95% CI = 1.34–3.68). The strongest association was found for stomach cancer [RRmedium = 1.17 (95% CI = 0.37–3.70), RRhigh = 3.13 (95% CI = 1.17–8.39)]. Exposure to carcinogens did not modify the effect of CA levels on overall cancer risk. These results reinforce the evidence of a link between CA frequency and cancer risk and provide novel information on the role of aberration subclass and cancer type.

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A high level of chromosomal aberrations in peripheral blood lymphocytes may be an early marker of cancer risk, but data on risk of specific cancers and types of chromosomal aberrations (chromosome type and chromatid type) are limited. A total of 6,430 healthy individuals from nine laboratories in Croatia, Hungary, Lithuania, Poland, and Slovakia, included in chromosomal aberration surveys performed during 1978-2002, were followed up for cancer incidence or mortality for an average of 8.5 years; 200 cancer cases were observed. Compared with that for the low-tertile level of chromosomal aberrations, the relative risks of cancer for the medium and high tertiles were 1.78 (95% confidence interval: 1.19, 2.67) and 1.81 (95% confidence interval: 1.20, 2.73), respectively. The relative risk for chromosome-type aberrations above versus below the median was 1.50 (95% confidence interval: 1.12, 2.01), while that for chromatid-type aberrations was 0.97 (95% confidence interval: 0.72, 1.31). The analyses of risk of specific cancers were limited by small numbers, but the association was stronger for stomach cancer. This study confirms the previously reported association between level of chromosomal aberrations and cancer risk and provides novel information on the type of aberrations more strongly predictive of cancer risk and on the types of cancer more strongly predicted by chromosomal aberrations.

Mutagen sensitivity, measuring the extent of chromosome damage induced by an in vitro treatment of peripheral lymphocytes with bleomycin, has been associated with an increased risk of various human cancers. Sensitivity to bleomycin appears to have high heritability and is usually considered to reflect individual capacity to repair DNA lesions. Another potential contributor to variation in bleomycin sensitivity could be inherited differences in the metabolism of bleomycin. We assessed whether genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes (XMEs) could explain bleomycin sensitivity. Frequencies of bleomycin-induced chromatid breaks per cell (b/c) were determined for 80 healthy Caucasians. Genotypes of DNA repair genes XRCC (X-ray repair cross-complementing) 1 and 3 and XME genes bleomycin hydrolase (BLHX), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and N-acetyltransferase 2 (NAT2) were analyzed from leukocyte DNA using methods based on polymerase chain reaction. The mean number of chromatid b/c was increased in individuals with XRCC1 codon 280 variant allele (P = 0.002; two-sided Mann-Whitney test). Smokers carrying BLHX codon 1450 variant allele showed a decrease in the mean number of chromatid b/c (P = 0.036). In multiple linear regression models including adjustment for age, sex, smoking and genotype, the adjusted relative risks (and 95% confidence intervals) were 1.18 (0.98-1.41) and 0.84 (0.69-1.00) for carriers of XRCC1 codon 280 and BLHX codon 1450 variant alleles, respectively. XRCC1 codon 280 polymorphism had a significant effect (P = 0.012) in predetermining whether the individual was classified as non-sensitive, sensitive or hypersensitive to bleomycin. Although based on relatively few individuals, our results suggest that bleomycin sensitivity is partially explained by genetic polymorphisms affecting DNA repair (XRCC1) and in vitro metabolism of bleomycin (BLHX).

Head and neck cancers are causally related to alcohol consumption, but the underlying mechanisms are unclear. Ethanol is metabolized to acetaldehyde, an experimental carcinogen. Quantitation of the major DNA adduct of acetaldehyde, N 2 -ethylidenedeoxyguanosine, in human tissues could help to elucidate the mechanism of alcohol carcinogenicity. We applied a quantitative method for the analysis of this adduct, measured as the NaBH 3 CN reduction product N 2 -ethyldeoxyguanosine (N 2 -ethyl-dGuo) by liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring, on DNA (0.04 F 0.03 mg) isolated from blood collected from control subjects recruited from two studies conducted in different areas of Europe between 1999 and 2005. The group selected from the first study (n = 127) included alcohol drinkers and abstainers while the group from the second study (n = 50) included only heavy drinkers. N 2 -ethyl-dGuo was detected in all DNA samples. After adjusting for potential confounders, in the first study, drinkers showed a higher level of N 2 -ethyldGuo (5,270 F 8,770 fmol/Mmol dGuo) compared with nondrinkers (2,690 F 3040 fmol/Mmol dGuo; P = 0.04). A significant trend according to dose was observed in both studies (P = 0.02 and 0.04, respectively). Taking into account the amount of alcohol consumption, adduct levels were higher in younger compared with older subjects (P = 0.01), whereas no differences were observed comparing men with women. These results show the feasibility of quantifying N 2 -ethyl-dGuo in small-volume blood samples and are consistent with the hypothesis that ethanol contributes to carcinogenesis through DNA adducts formation. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3026 -32)