Relationship between spontaneous frequency of aneuploidy and cancer risk in 2145 healthy Hungarian subjects.

Numerical and structural chromosomal abnormalities are the hallmarks of cancer. Whereas the structural chromosome aberrations got more substantial attention for cancer risk assessment in a healthy population, the role of aneuploidy is much less understood in this respect. We analysed the frequency of numerical (and structural) aberrations in peripheral blood lymphocytes of 2145 healthy individuals between 1989 and 2010, taking into account different biological- and exposure-conditions. We also studied to what extent chromosome gains or losses may predict the probability of cancer. The average frequency of all aneuploid cells was 1.78±0.06% in the entire study population, which increased linearly with age. Gender and smoking did not influence the values, however, occupational exposures did. The highest frequency of aneuploidy was found in chemical industry-workers (1.89±0.05%) compared with the lowest value of medical radiation workers (1.44±0.10%), respectively. No correlation was found between numerical and structural chromosomal aberrations. Cancer incidence followed for 1-23 years after the chromosome analysis showed a 1.26-fold relative risk (confidence interval: 1.02-1.58; P = 0.04) for those with higher frequency of aneuploid cells (1.82% vs. 1.44% in controls). Hypodiploidy had higher impact on the cancer risk than hyperdiploidy (1.72% vs. 0.10%). Our findings on the frequency of numerical aberrations in a healthy cohort represent the largest cytogenetic database from one laboratory with an unchanged mechanistic scoring method during a 30-year period, and provide basic information not only for genotoxicological studies but also confirm the association between numerical aberrations and cancer risk.

Frequency of Acentric Fragments Are Associated with Cancer Risk in Subjects Exposed to Ionizing Radiation.

BACKGROUND/AIM: Biomonitoring is currently applied in the estimation of health risks after overexposure to ionizing radiation (IR). The aim of this study was to compare the association of dicentric chromosomes and acentric fragments (AF) with cancer risk in subjects exposed to IR, as well as in control subjects. MATERIALS AND METHODS: The study was performed on 3,574 subjects (2,030 subjects exposed to IR and 1,544 control subjects). The mean follow-up period was 8 years. RESULTS: In subjects reporting exposure to IR, the presence of AFs and dicentric chromosomes was associated with a significant increase in cancer risk, hazard ratio (HR)=1.78 (95% confidence interval (CI)=1.01-3.13) and HR=1.73 (95% CI=1.03-2.90), respectively. CONCLUSION: AFs are associated with cancer risk and have a similar sensitivity to dicentric chromosomes in subjects exposed to IR. Because automated AF scoring can be easily introduced using fast flow cytometry combined with the pan-centromere staining, this biomarker may hold promise as a potential sensitive biomarker of exposure to IR and cancer risk.

[Serving biological dosimetry for 4 decades]. / A hazai biológiai dozimetria szolgálatában, a kezdetektõl napjainkig.

The author provides a comprehensive picture on introduction and application of chromosome biodosimetry in Hungary for measuring and estimation of biological doses of ionizing radiation. She describes different mathematical equations existing between the frequencies of dicentric and ring chromosome aberrations, and the different radiation doses of various radiation sources which form the basis of the method. She presents examples for estimation of biological doses received at radiation accidents, or cumulated during residential and occupational exposures in Hungary. The method of chromosome dosimetry is also offered to be used in radiotherapy because it allows the calculation of whole-body equivalent biological doses, and the determination of individual radiosensitivity as well, which cannot be fully informative by sole physical dose measurements. Dose-effect relationship in partial body irradiation might be affected by not only therapeutic doses, but also the localization and the volume of irradiated area of the body. In case of the same radiation therapy protocols and clinical features of the patients up to 2.5-fold differences in individual radiosensitivity may occur. Finally, the author analyzes the future state of biological dosimetry, the advantages and disadvantages of the methods to ensure determination of individual radiosensitivity, thereby administration of individualized radiotherapy.

[Frequency of spontaneous aneuploidy in the healthy Hungarian population]. / A spontán aneuploidia gyakorisága egészséges magyar populációban.

Aneuploidy plays very important role in tumor development as the consequence of either congenital or acquired mutations. In order to evaluate the adverse effects of various aneugens, the knowledge of the spontaneous frequency of numerical chromosome abnormalities in healthy population is fundamental. In our study we analyzed the spontaneous rate of numerical and structural chromosome aberrations in peripheral blood lymphocytes of 2145 healthy individuals, with special attention to the influence of biological (gender, age) and life-style factors (smoking, different occupational exposure). Correlation between aneuploidy and risk of cancer development were investigated according to National Cancer Registry data followed for 1-23 years. In the whole population the average frequency of aneuploid cells was 1.77±0.06%. This value increased by age linearly (r2=0.81) regardless of occupational exposures. Gender (biological factor) or smoking (life style factor) did not influence the values, however, the occupation of individuals modified the frequency of numerical aberrations. Individuals who worked at workplaces with radiation hazard had the lowest (1.44±0.10%), and those working in the chemical industry had the highest (1.89±0.05%) values of aneuploidy, respectively. We could not find any correlation between numerical and structural chromosome aberrations. In our population studied 97 individuals developed cancer and only those who had ≤2% aneuploidy survived more than 12 years in good health conditions. To our knowledge, this study has the highest case number investigated up to now. Our results support that aneuploidy, similarly to structural chromosomal aberrations, might be an additional cytogenetic biomarker of the genetic instability.

No short-term cytogenetic consequences of Hungarian red mud catastrophe.

Red mud is an industrial waste produced in the process of alumina extraction from bauxite with concentrated NaOH. When the red mud-containing reservoir collapsed in Ajka Alumina Plant Hungary in October 2010, the most serious immediate effects were caused by the high alkalinity (pH ≥ 13) of the flood. Many persons suffered burn-like damage to tissues and contact with caustic desiccated ultra-fine dust with traces of toxic metals also caused irritation of upper respiratory tract and eyes. This catastrophe was unique from the point of view of genotoxic effects as well. Therefore cytogenetic examinations were carried out on inhabitants, either with burns (17 persons) or on those inhaling desiccated caustic dust (42 persons). Chromosomal aberration (CA) analysis and bleomycin (BLM)-sensitivity assays, as possible markers of effects, were studied in peripheral blood lymphocytes of persons within 4-6 weeks following the catastrophe. Controls were matched for age, sex and smoking habits, and also places of residence with different constituents of air pollution either from rural (59 persons), or from urban environments (59 persons). Neither spontaneous rate of CAs (1.47% vs. 1.69%) nor BLM-induced in vitro chromosomal breakage (0.79 vs. 0.83 break/cell) showed elevated rates when cytogenetic biomarkers of genotoxicity were compared between controls and exposed persons. Time spent in cleaning did not affect cytogenetic changes either (R(2) = 0.04). BLM-induced mutagen sensitivity was similar in exposed and control persons (27.1% vs. 30.5%). It seems that the red mud exposure does not appear to pose an immediate genotoxic hazard on residents when measured with cytogenetic methods. We recommend, however, that those involved in clean-up activities should be followed closely not only for overall health, but also for further genotoxic risk assessment, because the long-term hazards of ultra-fine fugitive dust particles with alkalinity of residual NaOH in red mud are still unknown.

N2-ethyldeoxyguanosine as a potential biomarker for assessing effects of alcohol consumption on DNA.

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, N2-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 NaBH3CN reduction product N2-ethyldeoxyguanosine (N2-ethyl-dGuo) by liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring, on DNA (0.04 +/- 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. N2-ethyl-dGuo was detected in all DNA samples. After adjusting for potential confounders, in the first study, drinkers showed a higher level of N2-ethyl-dGuo (5,270 +/- 8,770 fmol/micromol dGuo) compared with nondrinkers (2,690 +/- 3040 fmol/micromol 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 N2-ethyl-dGuo in small-volume blood samples and are consistent with the hypothesis that ethanol contributes to carcinogenesis through DNA adducts formation.

[Problems occurring in the application of cytogenetic biomarkers for alcoholics with and without malignant diseases]. / Biomarkerek alkalmazása során felmerülo problémák malignus és nem malignus betegségben szenvedo alkoholisták esetében.

Applicability of alcohol- and smoking-related cancer-risk biomarkers might be modified by several factors. Among those, reality of self-reports on alcohol consumption of alcoholic patients with different diseases and extreme high mutagen hypersensitivity of Hungarians, as well as the immunologic role of peripheral lymphocytes as experimental objects of cytogenetic biomarkers seem to be new viewpoints of interest. To clarify these problems, 432 head and neck cancer patients (HNCP), 62 alcoholics with alcoholic hepatitis (ALCL), and 101 disease-free chronic alcoholics (ALC) were examined. Despite clinically confirmed alcohol-related diagnoses (and GGT and MCV values) only about half of HNCPs and ALCLs reported about any alcohol consumption, in contrast to the realistic self-reports of ALCs. In cytogenetic case control investigations no difference between the spontaneous rate of chromosomal aberrations (CAs) of healthy controls and ALCs was found, however, genetic instability expressed as a 40-50% elevation rate of CAs in HNCPs and ALCLs might be associated with systemic inflammatory reaction of lymphocytes. Bleomycin sensitivity assay showed the highest break/cell (b/c) values not in HNCPs (1.06 b/c) as it was reported earlier, but in "healthy" ALCs (1.52 b/c). This phenomenon can be related to the local effect of genotoxins (alcohol, smoking, and in particular the diet), which probably reflects merely a reaction of mucosal immune system. Nearly 50% of mutagen-hypersensitive Hungarian controls, in contrary to the expected 10-20% ones, might also be explained by this. Similarly, HNCPs with oral cancer, where the local mutagen effect was the most intensive, had the highest b/c values. In conclusion, when cytogenetic biomarkers of alcoholism are examined, the subjective character of self-reports at epidemiologic level and immunologic role of lymphocyte subpopulations as genetic confounders must also be taken into consideration.

Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22 358 subjects in 11 countries.

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 [RR(medium) = 1.17 (95% CI = 0.37-3.70), RR(high) = 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.

Increase of hypophyseal hormone levels in male head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) develops in at least 80% of cases in men with a history of smoking and heavy alcohol consumption, still it is only diagnosed in a small proportion of alcoholics. Endocrine milieu is an important factor in carcinogenesis and prognosis of several cancer types. The aim of our study was to investigate sex steroid and hypophyseal hormone status of male HNSCC patients in comparison to healthy volunteers and to patients with alcoholic liver disease, to determine possible hormonal alterations characteristic of cancer. Liver function (GGT level), and serum levels of gonadotropic hormones (FSH, LH, prolactin), sex steroids (estradiol, progesterone, testosterone) and sex hormone-binding globulin (SHBG) were compared in 130 male HNSCC patients, 54 patients with alcoholic liver disease but no known cancer, and 56 healthy controls. We found abnormal values of liver function in both HNSCC patients and alcoholics compared to healthy controls, suggesting the presence of alcoholic liver disease in the former group as well. On the other hand, a significant elevation in the level of DHEA, FSH and LH was observed in cancer patients exclusively. As a conclusion, abnormal alterations in sex steroid hormone levels can frequently be found in HNSCC patients, which may be caused in part by the alcoholic liver damage accompanying the disease. The significant increase in FSH and LH serum levels, observed only in the cancer patients, indicates that these hormones may play a role in the development and/or progression of HNSCC.

Chromosomal aberrations and cancer risk: results of a cohort study from Central Europe.

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.

[The role of chemical and physical factors in cancer development]. / Kémiai és fizikai tényezôk szerepe a daganatok kialakulásában.

The author deals with the effects of environmental chemical-, and physical carcinogens playing predominant role in nearly 90% of the cancer development. Different steps of chemical carcinogenesis, classification and evaluation of carcinogens according to the criteria of International Agency for Research on Cancer, and the most important biological markers of genotoxic exposures are presented. Among physical agents the carcinogenic effects of ionizing and nonionizing radiations are demonstrated, including limited, inadequate or proved carcinogenic action of UV, microwave, static and low-frequency electric and magnetic fields.

Mutagen sensitivity of patients with cancer at different sites of the head and neck.

In the aetiology of head and neck squamous cell carcinoma (HNSCC), smoking and heavy alcohol consumption are the main environmental risk factors. The bleomycin (BLM) sensitivity assay is believed to measure environment-related cancer risks, mainly of HNSCC. Previously, we have shown that this method is only moderately sensitive to identify individuals at high risk for developing HNSCC, due to broad overlap of BLM-induced chromatid breaks per cell (b/c) between cancer patients and controls, and alcoholics with liver diseases. In the present study, we evaluated whether the differences between patients and controls are more manifested when the risks according to localization of HNSCC are examined. BLM sensitivity in lymphocytes of 278 patients with HNSCC at four different anatomical sites, and that of 356 frequency-matched controls was studied. There was a significant difference in BLM-induced b/c values between patients (1.11 b/c) and controls (0.97 b/c); however, considering all HNSCC cases, only 58.3% of patients and 43.3% of controls were mutagen sensitive. When the patients were distributed according to tumour sites, mutagen sensitivity of those with cancer of oral cavity, oropharynx and hypopharynx was significantly higher than that of the frequency-matched controls (1.12-1.14 b/c versus 1.00 b/c), while laryngeal tumour patients (1.05 b/c) did not differ from controls (1.00 b/c). When the associations between BLM sensitivity and the risk of HNSCC sites were examined, it was expressed mostly in patients with tumours of the oral cavity and oropharynx (OR = 1.97 and OR = 1.90), and not in patients with tumours of the hypopharynx and larynx. Though the mutagen sensitivity decreased from the oral cavity down to the larynx, indicating that the site-specific risks may differ, the BLM assay shows weak and controversial associations between mutagen sensitivity and cancer risk of patients even at specific HNSCC sites.

Increased predisposition to cancer in brothers and offspring of testicular tumor patients.

Cancer susceptibility was examined in first-degree relatives of 293 testicular tumor patients (TTPs) and 586 age-matched healthy males. Significantly increased risk was found in the families of TTPs (OR: 1.4; CI: 1.08-1.79), however, except for testicular cancer of 7 brothers (OR: 11.7; CI: 1.42-256.5), and 6 various childhood tumors (bilateral Wilms' tumor, neuroblastoma, medulloblastoma, ALL, histiocytosis-X, testicular tumor) of 200 offspring (OR: 12.9; CI: 1.54-286.2), no association with other malignancies was observed. No differences were seen between the fertility of patients and controls when occupational or socio-economic status of the families was taken into account. However, the majority of the controls (85%) fathered the first child between 20-30 years of age, while only 61% of TTPs had the first child in the same age group. TTPs fathered more girls than boys (P=0.009), and the lower male - higher female ratio of index children was also identical, irrespective of the conception taking place before or after the father's treatment. Occupations did not, but smoking might have influenced cancer susceptibility of the patients. Aggregation of fraternal testicular tumors, and both dramatically increased cancer risk and altered sex ratio of the offspring indicate a remarkable role of hereditary factors in tumorigenesis and later consequences of a certain portion of testicular malignancies, which must be refined by molecular studies.

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: effects on levels of sister chromatid exchanges and chromosomal aberrations.

Elevated levels of chromosomal aberrations (CAs) in peripheral blood lymphocytes, widely used as a cytogenetic biomarker of genotoxic effects, have been linked to cancer predisposition. However, tobacco smoking, occupational carcinogen exposure, or time since CA analysis do not appear to explain the cancer predictivity of CAs. Alternatively, the observed CA-cancer association could reflect unidentified exposures or individual susceptibility. We assessed the effects of genetic polymorphisms of DNA repair proteins and xenobiotic-metabolizing enzymes (XMEs) on the levels of CAs and sister chromatid exchanges (SCEs) in peripheral lymphocytes of 145 (CAs) and 60 (SCEs) healthy Caucasians. Genotypes of DNA repair genes X-ray repair cross-complementation group 1 (XRCC1 codons 194, 280, 399) and 3 (XRCC3 codon 241 [corrected]), and XME genes glutathione-S-transferase (GST) M1 and T1 and N-acetyl transferase 2 (NAT2) were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP)-based methods. After Poisson regression adjustment for age, sex, smoking, country, and genotypes, a higher frequency of chromosome-type breaks was observed for NAT2 slow acetylators (in nonsmokers) and GSTT1 null subjects (in smokers). Individuals carrying variant alleles for XRCC1 codons 280 and 194 showed a decreased level of chromosome-type breaks. The effect of GSTM1 null and XRCC1 codon 399 genotypes on the frequency of CAs was modified by smoking. In linear regression models adjusting for age, sex, smoking, and genotypes, none of the polymorphisms significantly affected SCE frequency, although GSTT1 null subjects had a slightly elevated SCE level. Our results are in line with earlier findings on the influence of NAT2, GSTT1, and GSTM1 polymorphisms on the level of lymphocyte chromosome damage and suggest that also XRCC1 polymorphism affects CA frequencies, thus apparently influencing DNA repair phenotype. It remains to be examined whether these or other genetic polymorphisms could explain the observed cancer risk predictivity of high CA frequency.

[Prognostic significance of sex steroid and hypophyseal hormones in head and neck squamous cell carcinoma]. / Szex szteroid- és hypophysishormonszintek prognosztikus jelentôsége fej-nyaki laphámrákban.

OBJECTIVE OF THE STUDY: to investigate the clinical outcome of HNSCC patients, and their hormonal status. METHOD: The liver function (GGT), hypophysis gonadotrop hormone (FSH, LH, prolactin) and sexsteroid hormone serum levels were examined in 130 male HNSCC patients. Clinical parameters for age, primary tumor site and clinical tumor stage were also recorded. RESULTS: The survival was disadvantageously influenced by the following parameters: age, the presence of lymph node metastasis, advanced tumor stage, the lower than normal testosterone and the higher than normal FSH serum levels. CONCLUSION: Elevated FSH and decreased testosterone serum levels showed significant correlation with the survival of head and neck cancer patients. The better understanding of their exact role in the biology of HNSCC requires further investigations.

[Sporadic chromosome aberrations in healthy individuals studied between 1986-2001]. / A sporadikus kromoszómaaberrációk alakulása 1986-2001 között vizsgált egészséges személyek limfocitáiban.

In the second half of 2002, IARC for Central and Eastern European countries targeted studies on the relationship between chromosomal aberrations (CAs) and cancer risk. For these purposes we preliminarily investigated, under identical methodological circumstances, the base-line level of CAs in peripheral blood lymphocytes of 1414 healthy Hungarian persons between 1986 and 2001. The age and sex as biological, and smoking habit and residency (Budapest, industrial- and agricultural settlements) as environmental confounding factors were evaluated. Previously, people were not exposed to any known potential mutagens. The overall frequencies of aberrant cells (1.60+/-0.05%) were not influenced by sex, age and residency, but the smoking habits (1.84+/-0.09%) had significant impact on the elevation of aberrant cells. Aneuploidy, exchange-type dicentric chromosomes and the total of aberrations increased significantly with the age of the donors. The individual frequency of aberrant cells ranged between 0-12%. No aberrant cells were detected in 35% of individuals, and 1 aberrant cell was found in 23% of the total population, while 42% of the examined persons were characterized with aberrant cell rates between 2-12%. The initial value of 0.85% of aberrant cells doubled by the end of the examined 16-year period, following 2-4-fold fluctuations. None of the investigated biological or environmental factors was responsible for the elevation of the CAs. The causes of the elevation of CA-level can be explained more precisely when these data will be compared to cancer registry database of these persons.

Does the bleomycin sensitivity assay express cancer phenotype?

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 >or=2% and b/c is >or=1.

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity.

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).

[Serum levels of sex steroid and pituitary hormones in chronic alcoholics and head and neck cancer patients as compared to normal controls]. / Szex szteroid- és hypophysishormonok valamint a májfunkció összehasonlító vizsgálata egészséges, alkoholista és fej-nyaki laphámrákos férfiakban.

UNLABELLED: Head and neck squamous cell carcinoma (HNSCC) is diagnosed mainly in male patients (more than 80% of the cases) with a history of smoking and heavy alcohol consumption. However, only a few percent of all alcoholics develop head and neck cancer. OBJECTIVE OF THE STUDY: to investigate the hormonal status in HNSCC patients as compared to healthy controls and alcoholic persons in order to find changes, if any, characteristic for cancer. METHOD: The liver function expressed by gamma-GT levels, the hypophysis gonadotrop hormone (FSH, LH, prolactin) and sex steroid hormone serum levels were examined in 130 male HNSCC patients, in 54 men with alcoholic liver disease but without any known cancer and in 56 healthy men as controls. RESULTS: When compared to the healthy controls, both alcoholics and tumor patients had abnormal liver function, testosterone, sex hormone binding globuline and prolactin levels, reflecting the presence of alcoholic liver disease in tumor patients as well. However, abnormally elevated circulating FSH (p<0.005) and LH (p<0.0003) levels were present only in the tumor patients. CONCLUSION: Sex steroid hormone abnormalities are common among head and neck cancer patients, mainly as results of the chronic alcoholic liver disease. Elevation of FSH and LH levels suggests a potential role of these hormones in the formation of head and neck cancer. The exact role of the hypothalamus-hypophysis-liver axis in the biology of head and neck cancer requires further investigations.