Mutagenesis, Vol. 18, No. 1, 59-63,
January 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Does the bleomycin sensitivity assay express cancer phenotype?
1 Department of Oncocytogenetics and 2 Department of Head and Neck Surgery, National Institute of Oncology, Ráth Gy. u. 7–9, H-1122 Budapest, Hungary
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Abstract |
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The bleomycin (BLM) sensitivity assay has been associated with the measuring of increased risk of individual susceptibility to cancer, when chromatid breaks per cell (b/c) induced by an in vitro treatment of lymphocytes with BLM are elevated. The high heritability of BLM sensitivity indicates a genetic background. We wished to clarify whether the test characterizes the head and neck cancer phenotype as compared not only with healthy individuals, but also with alcoholic patients (ALCs) whose exposure to tobacco and alcohol consumption were similar to that of head and neck cancer patients (HNCPs), but whose liver diseases were not cancerous. If the BLM test quantifies merely cancer susceptibility on an inherited basis, the mutagen sensitivity of HNCPs should differ from that of ALCs. Conventional chromosome analysis and the BLM assay were carried out on 156 HNCPs, 51 ALCs, 146 healthy non-smokers and non-drinkers and 149 non-drinking smokers. The spontaneous rates of chromosomal aberrations (CAs) in HNCPs, ALCs and healthy smokers were identical (2.8%), but differed significantly from the non-smoking controls (2.25%). Sporadic CAs were clearly associated with tobacco smoking, but not with health status. Mutagen sensitivity measured by the BLM test showed significantly (P < 0.04) elevated values not only in HNCPs (1.13 b/c), but also in ALCs (1.29 b/c) as compared with the controls (1.01 b/c). The main finding of the study was that a considerable proportion (46%) of Hungarian controls were mutagen sensitive, twice as many as in those populations reported by others so far. Our data suggest that the BLM test does not characterize susceptibility to cancer due to insignificant differences between HNCPs and ALCs (P = 0.12) under our conditions. However, the assay might be used as a biomarker to predict cancer susceptibility under circumstances when aberrant cell frequency is
2% and b/c is 1. |
Introduction |
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Hungarians have the lowest life expectancy and the highest rate of cancer mortality in Europe (Landis et al., 1998
). These phenomena can principally be related to extensive environmental pollution over the past decades and the self-destructive behaviour of the population (Gundy, 1995; Mackenbach et al., 1999; Kopp and Csoboth, 2001). One of the most alarming trends can be observed in the mortality rate of head and neck squamous cell carcinomas, mostly due to long-term tobacco and alcohol use. Alcohol abuse equal to 11 l of absolute alcohol/capita/year on average is one of the highest in Europe (KSH, 2000). The prevalence of smoking is also high, at 46–49% of men in a national representative survey (Kopp and Csoboth, 2001). The increase in death rate from head and neck cancer will double by the end of year 2004 compared with the data for 1994, as stated in the WHO predictions (Bray et al., 2000). The dramatic increase in mortality due to head and neck cancers in Hungary points to the importance of primary and secondary cancer prevention. Therefore, the search for appropriate biomarkers as tools in prevention programmes is essential.
In recent years Hsu and co-workers have developed an in vitro biomarker assay for the estimation of individual genetic susceptibility to cancer. The method is based on the scoring of bleomycin (BLM)-induced chromatid breaks occurring in cultured lymphocytes in vitro in the late G2 phase of the cell cycle. It has also been shown that the cells of cancer-prone persons insufficient in DNA repair respond with an elevated number of chromatid-type breaks (Hsu et al., 1985, 1989; Cloos et al., 1996; Spitz et al., 1996; Michalska et al., 1998; Wu et al., 1998b). The greatest sensitivity to BLM was found in >70% of patients with cancers of organs directly exposed to the external environment and there was only ~10–20% of healthy individuals who were hypersensitive in this respect (Hsu et al., 1989; Cloos et al., 1996).
The development of head and neck cancer is also highly related to the exposure of external environmental factors. However, exposure to tobacco and alcohol are the main aetiological determinants not only in head and neck squamous cell carcinomas but also in alcohol-related liver diseases (Blot et al., 1988). Our cardinal question was whether the BLM assay is able to measure mutagen sensitivity and thus cancer phenotype in head and neck cancer patients (HNCPs) compared not only with healthy individuals, but also with alcoholic patients (ALCs) whose environmental and lifestyle exposures are similar to those of HNCPs, but whose liver disease is not cancerous. If we suppose that the BLM assay quantifies merely cancer susceptibility on a genetic basis, as is presumed by several authors (Hsu et al., 1989; Spitz and Hsu, 1994; Cloos et al., 1996, 1999; Yu et al., 1999), then the mutagen sensitivity of HNCPs should somehow differ from those developing `only' alcoholic liver diseases.
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Materials and methods |
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Study subjects
Conventional chromosome analysis and the BLM test were studied in 156 histologically confirmed untreated HNCPs (mean age 54.3 ± 9.8 years) with cancers of the lip, tongue, pharynx and/or larynx and 51 untreated cancer-free ALCs suffering from alcoholic cirrhosis and fatty degeneration of the liver (mean age 53.3 ± 11.0 years). Human papilloma (HPV) and Epstein–Barr viruses were diagnosed in neither patient group. All HNCP and ALC patients were smokers and drinkers. They smoked >15 cigarettes/day and drank >3 IU alcohol/day (1 IU is defined as equivalent to 15 ml of absolute alcohol). Patients had been drinking alcohol for at least 5 years and had been smoking cigarettes for at least 10 years before sampling. Others with uncertain anamnesis were excluded from the study, therefore subdivision according to smoking and alcohol consumption habit was not made (several HNCPs and ALCs generally tried to minimize their true smoking and drinking habits at the time of taking the history).
As controls, 146 non-smokers (mean age 53.4 ± 9.2 years) and 149 non-drinking smokers (mean age 53.3 ± 9.1 years) were examined. The smoking habits of the latter group were similar to those of the patient groups (HNCPs and ALCs). The ratio of males to females was the same in each group (9:1). Non-smoking drinkers constituted <1% of the study population, therefore, they were excluded from the study.
Blood sampling, culturing and chromosome analysis
Conventional chromosome analysis.
Blood sampling, cultivation and chromosome preparation were carried out in duplicate by standardized methods described previously (Gundy et al., 1996). Cells were incubated for 48 h. The slides were coded and the chromosomal aberrations (CAs) were evaluated by four well-trained scorers. For the past 10 years the interscorer variability has not exceeded 1% in our laboratory. The aneuploid cells contained 46 ± 1 chromosomes.
BLM sensitivity assay.
The BLM test was applied according to the protocol described by Hsu et al. (1989). Briefly, we followed the procedure of conventional blood culture, however, the lymphocytes were incubated for 72 h until second cell divisions resulted. Five hours before harvesting, two sets of cultures were treated with BLM (30 µg/ml) and with colcemid during the last 2 h, respectively. Following conventional cell harvest Giemsa staining was applied. One hundred metaphases per person were counted during the whole study.
The mean number of chromatid breaks per cell (b/c) was used as an indicator of mutagen sensitivity. Similarly to others (Hsu et al., 1989; Cloos et al., 1996), we found that the scoring of gaps did not influence the outcome of the mutagen sensitivity and thus it was omitted in further investigations. Background levels of chromosome-type aberrations in G2 of the second mitosis were very low, and thus negligible, in all groups.
The limit of the hypersensitivity to mutagen was considered as the value of the third quartile (Wu et al., 1998a). Thus, 1.25 b/c was taken as an arbitrary cut-off for mutagen hypersensitivity and values between 1.0 and 1.24 b/c indicated the proportion of intermediately sensitive persons. The cut-off for mutagen sensitivity overall was determined at b/c 1.
Combined use of conventional chromosome analysis and BLM sensitivity assay.
In order to determine the relationship between the rate of spontaneous CAs and degree of mutagen sensitivity measured by the BLM test, the group data were dichotomized so that b/c 1 was taken as a cut-off for mutagen sensitivity and different cut-off points (1–4%) were used for aberrant cells.
Statistics
The normal distribution of all examined groups were investigated according to the Kolgomorov–Smirnov test. CAs were statistically analysed by the Wilcoxon test (Major et al., 1998). Student's t-test was used to compare b/c means between the groups (Cloos et al., 1996). The influence of age and smoking on b/c ratios was tested by a multiple regression method (Michalska et al., 1998). The associations between mutagen sensitivity, spontaneous rates of CAs and cancer risk were estimated by odds ratios (ORs) with 95% confidence intervals (CIs). In order to calculate the ORs we compared the highest quartile of subjects with the lowest one. All P values were determined on the basis of two-sided tests and P < 0.05 was considered the limit of significance. All analyses were performed using the GraphPad Instat (v.3.05, 2000) and GraphPad Prism (v.3.02, 2000) computer programs (GraphPad Software, Inc.).
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Results |
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Spontaneous rate of chromosomal aberrations
The results of conventional chromosome analysis are shown in Table I
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Chromosome-type fragments and dicentric + ring chromosomes showed very similar frequencies in all groups (P > 0.09), independent of smoking habit and health status of the subjects. However, the lowest frequencies of chromatid breaks and aberrant cells were measured in non-smokers, indicating that the spontaneous rate of CAs is clearly associated with the mutagenic effect of tobacco use (P < 0.04), but not with alcohol consumption and health status (P > 0.05).
Bleomycin sensitivity assay
Mutagen sensitivity measured by the BLM test was not influenced (P > 0.20) by age, gender or smoking alone (data are not shown). When the distribution profile of BLM sensitivity in terms of 0.4 increments in average b/c was established in each group, we found a wide variability among all subjects (Table II). There was a much broader range of b/c values in the HNCPs and ALCs than in the controls (0.23–3.35 versus 0.13–2.46) and no difference was found between non-smoking and smoking controls (P = 0.24). Concerning average b/c values of different groups, both HNCPs and ALCs had significantly higher mean values (P < 0.04) than non-smokers and smokers (1.13 and 1.29 versus 0.98 and 1.04 b/c). There was no difference between HNCPs and ALCs (P = 0.12) in this respect, thus, it is apparent that not only cancer patients but also ALCs, irrespective of the malignant character of the disease, have similarly decreased repair capacity when compared with healthy controls.
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According to the results of dichotomization the value b/c
1 was applied as a cut-off point for the determination of mutagen sensitivity. In this case 65% of HNCPs and 59% of ALCs and a rather high proportion of non-smokers (43%) and smokers (49%) could be classified as mutagen-sensitive persons. We tested other cut-off points to separate BLM-sensitive persons from resistant ones, but the values for the controls overlapped considerably with the values of the diseased patients. Thus we kept b/c 1 as the best limit value for all sensitive individuals and b/c < 1 for insensitive ones.
The relationship between rates of spontaneous aberrations and BLM sensitivity
Since there was a relatively high proportion of sensitive persons among smokers and non-smokers and the mean values of b/c did not differ significantly between the cancer patients and ALCs, we tried to find a mean to distinguish more markedly between the cancer phenotype and the non-cancerous one. The two cytogenetic biomarkers were, therefore, applied together (Table III). When b/c 1.0 was used as the cut-off point for mutagen sensitivity there was a small but significant association with increased risk of cancer in HNCPs compared with all (OR = 2.18) and smoking controls (OR = 1.91). Although the proportion of mutagen-sensitive persons is statistically lower among smokers (49%) than among HNCPs (64.7%), this difference is too small to distinguish between the genetic sensitivities of the two study groups when specific biomarkers are searched.
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The groups examined were further dichotomized so that b/c
1.0 was taken as the cut-off for mutagen sensitivity with different cut-off points (1–4%) for aberrant cells. First we compared HNCPs with age- and sex-matched smoking controls (Table III
), since all HNCPs were also smokers. The best OR (2.13) was obtained when b/c was 1.0 and the aberrant cell frequency was 1%. In this case the proportion of sensitive persons still remained high among smokers (43.6%). When the cut-off point for aberrant cell frequency was 2%, the OR for cancer risk was still significantly high (1.62), but the proportion of sensitive individuals decreased to a greater extent (36.9%) than in the former case.
HNCPs were also compared with the age- and sex-matched whole control group, irrespective of smoking habit. ORs in this case had higher values than those in smoking controls. The higher the aberrant cell frequency, the greater was the OR, and the increase in cancer risk was inversely associated with the proportion of mutagen-sensitive controls. When b/c was 1.0 and the aberrant cell frequency was 2% the OR was still large enough, and the proportion of sensitive persons in matched controls was sufficiently small. Thus, the combination of two biomarkers gave more information about cancer risk than the BLM assay alone.
Besides HNCPs, the ALCs were also compared with the controls. The ORs were similar to those obtained for HNCPs, indicating that as far as cancer susceptibility is concerned, the BLM test does not separate HNCPs from ALCs (data are not shown).
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Discussion |
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The search of biomarkers for the identification of persons at risk of cancer is an important task in public health. The frequency of sporadic CAs is a relevant biomarker for the estimation of cancer risk in humans when increased yields of CAs are found in exposed and non-exposed groups of subjects (Hagmar et al., 1994
, 1998; Major et al., 1998; Bonassi et al., 2000). The BLM test is an independent intrinsic biomarker (Hsu et al., 1989; Spitz et al., 1989, 1996; Spitz and Hsu, 1994; Cloos et al., 1996) which is thought to meausure individual cancer risk on a genetic basis (Hsu, 1983; Wu et al., 1995; Cloos et al., 1999; Yu et al., 1999). Therefore, besides spontaneous CAs we introduced the use of the BLM assay as a new biomarker not before applied for cancer risk assessment in Hungary.
We compared the spontaneous rate of CAs and BLM-induced mean b/c values among diseased (HNCPs and ALCs) and healthy groups (smokers and non-smokers). Sporadic CAs were clearly associated with smoking, irrespective of alcohol consumption and health status. Thus, we concluded that this method is a suitable biomarker of genotoxic exposure to tobacco. On the other hand, significantly higher b/c values not only in HNCPs but also in ALCs in comparison with healthy controls indicated that the BLM assay seems to be a biomarker of both, i.e. continuous genetoxic exposure to high level tobacco use and alcohol consumption, and subsequent disease. The method does express an intrinsic susceptibility to disease, but not to cancer. Alcohol-related liver disease is a typical environment-related, but non-cancerous disease. The determinants of its aetiology bear similarities to those of head and neck cancer. Alcohol is likely to potentiate the mutagenic effect of smoking with temporary inhibition of DNA repair capacity (Hsu and Furlong, 1991) in both diseases, irrespective of their malignant character. In West European and US study groups smoking and alcohol use did not influence the b/c values in either controls or HNCPs (Cloos et al., 1996). However, there was a clear interaction between cancer risk and heavy exposure to tobacco and alcohol consumption in the same study.
We think that under certain circumstances the relationship between cancer susceptibility and mutagen sensitivity is not so unequivocal as reported by many (Hsu et al., 1989; Cloos et al., 1996; Gu et al., 1999). It seems that in HNCPs there are some unidentified genetic factors of cancer predisposition for which the BLM test is not sensitive enough. Similar potential mutagens and carcinogens and their metabolic products may activate different repair pathways leading either to cancer or to other disease (Bohr et al., 1989). Another explanation for the controversial inherited character of cancer susceptibility might be that the BLM sensitivity test has been used so far only to differentiate cancer patients from healthy persons.
When mean b/c values of HNCPs and healthy controls were compared, individual b/c values had greater variability within each group in our study than those demonstrated by other authors (Hsu et al., 1989; Michalska et al., 1998).
In the Hungarian study group the proportion of sensitive persons is extremely high: it constitutes 43% for non-smokers and 49% for smokers. This percentage is double that observed in the USA and in Western Europe (Hsu et al., 1989; Cloos et al., 1996). At the same time, 64.8% of our HNCP subjects were sensitive, correlating well with the figure (72.8%) observed by Hsu et al. (1989). Whatever cut-off points and mathematical approaches were used, the values for the controls overlapped considerably with the values for diseased patients.
Because of our doubts concerning the genetic basis of cancer susceptibility measured by the BLM test, we extended our examination to the combined use of counting spontaneous CAs and the BLM assay.
Under conditions when b/c was 1 and the aberrant cell frequency was 2%, the application of the two methods gave reasonable results. However, this combined method is time consuming and may restrict its routine use in cancer prevention programmes.
The reason for high mutagen sensitivity in our controls is not clear, but it harmonizes with the trend in Hungarian mortality statistics. Some genetic and cultural differences contributing to this phenomenon cannot be excluded. Numerous data support the idea that the sensitivity of some subpopulations may differ from that of other subpopulations for certain sporadic and hereditary cancers (Tompa and Sápi, 1989; Musilová et al., 1993; van der Looij et al., 2000). We cannot rule out that under various environmental conditions polymorphisms of repair and detoxification enzyme systems may modify mutagen sensitivity. Some authors reported remarkably high susceptibility to oral cancer of individuals with the genotypes CYP1A1 C and GSTM1- even at low dose levels of tobacco exposure (Sato et al., 1999; Tanimoto et al., 1999). Our studies on the role of enzyme polymorphisms are in progress. In one of our very recently published studies (Tuimala et al., 2002) the b/c values and frequencies of some DNA repair and xenobiotic-metabolizing enzymes were determined for 80 healthy Hungarians, but not for HNCPs. We found that smokers carrying a bleomycin hydrolase gene (BLHX) codon 1450 variant allele showed decreased b/c values. X-ray repair cross-complementing 1 gene (XRCC1) codon 280 polymorphisms had a significant effect in predetermining whether the individual was classified as non-sensitive or sensitive to BLM. We suggest that BLM sensitivity could partly be explained by genetic polymorphisms affecting DNA repair (XRCC1) and in vitro metabolism of bleomycin (BLHX).
In conclusion we may say that the BLM assay seems to be a tool for characterization of genotoxic exposure to heavy tobacco and alcohol use rather than for individual susceptibility to cancer. Possible ethnic variations and enzyme polymorphisms may contribute to the high mutagen sensitivity of Hungarians. The assay, however, might be used as a biomarker to predict cancer susceptibility under limited conditions, i.e. when the aberrant cell frequency is 2% and b/c is 1.
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Acknowledgments |
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We are grateful to Ms Nadja Vass and Miss Krisztina Kiss for their excellent technical assistance. This work was supported by national grants OTKA-024125, OTKA-034416 and NKFP/1/48.
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Notes |
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3 To whom correspondence should be addressed. Tel: +36 1 224 8779; Fax: +36 1 224 8776; Email: gundy{at}oncol.hu
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Received on February 11, 2002; accepted on August 19, 2002.
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