Genotype and haplotype analysis of TP53 gene and the risk of pancreatic cancer: an association study in the Czech Republic.

Pancreatic carcinoma is the fourth leading cause of cancer-related deaths in the Czech Republic, with only a minimum of patients surviving 5 years. The aetiology and molecular pathogenesis are still weakly understood. TP53 has a fundamental role in cell cycle and apoptosis and is frequently mutated in solid tumours, including pancreatic cancer. Based on the assumption that genetic variation may affect susceptibility to cancer development, the role of TP53 polymorphisms in modulating the risk of pancreatic cancer may be of major importance. We investigated four selected polymorphisms in TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T and rs17884306:G>A) in association with pancreatic cancer risk in a case-control study, including 240 cases and controls (for a total of 1827 individuals) from the Czech Republic. Carriers of the variant C allele of rs1042522 polymorphism were at an increased risk of pancreatic cancer [odds ratio (OR) 1.73; 95% confidence interval (CI) 1.26-2.39; P = 0.001]. Haplotype analysis showed that in comparison with the most common haplotype (A(1)GCG), the A(2)CCG haplotype was associated with an increased risk (OR 1.39; 95% CI 1.02-1.88; P = 0.034) and the A(1)CCG with a reduced risk (OR 0.30; 95% CI 0.12-0.76; P = 0.011) for this cancer. These results reflect previous findings of a recent association study, where haplotypes constructed on the same TP53 variants were associated with colorectal cancer risk [Polakova et al. (2009) Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic. Hum. Mutat., 30, 661-668.]. Genetic variation in TP53 may contribute, alone or in concert with other risk factors, to modify the inherited susceptibility to pancreatic cancer, as well as to other gastrointestinal cancers.

Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic.

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in the world. To assess the role of genetic variants on the disease, we genotyped polymorphisms in the TP53 (rs17878362:A(1)>A(2), rs1042522:G>C, rs12947788:C>T, and rs17884306:G>A), CDKN1A (rs1801270:C>A and rs1059234:C>T), and CDKN2A (rs3731249:G>A, rs11515:C>G, and rs3088440:C>T) genes in 614 hospital-based CRC cases and 614 matched controls from the country. Despite the tendency toward differential distribution of variant allele frequencies for some polymorphisms, none was significantly associated with CRC risk. We observed differential distribution of major haplotypes arising from four polymorphisms in the TP53 gene between cases and controls (global P<0.0001). The two most common haplotypes, A(1)GCG and A(2)CCG, were present in 81% of the cases compared to 71% of the controls. In comparison to the most common haplotype (A(1)GCG), the haplotype A(2)CCG was associated with an increased risk (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.07-1.82), while the four other haplotypes A(1)CCG (OR, 0.60; 95% CI, 0.45-0.79), A(2)GCG (OR, 0.53; 95% CI, 0.35-0.81), A(1)GTG (OR, 0.31; 95% CI, 0.15-0.64), and A(1)GCA (OR, 0.19; 95% CI, 0.07-0.51) were associated with a decreased risk. The effect of haplotypes in the TP53 gene was similar in colon (global P<0.0001) and rectal cancers (P=0.006). No association with the disease was observed with haplotypes of the CDKN1A and CDKN2A polymorphisms. The results from this study suggest that prevalent haplotypes within the TP53 gene may modulate CRC risks in the population.

DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic.

Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case-control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01-2.22; p=0.05). The data stratification showed increased risk of colorectal cancer in the age group 64-86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04-3.07; p=0.04) and homozygous (OR: 2.57; 95% CI: 1.30-5.06; p=0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17-15.54; p=0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40-29.02; p=0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene-gene and gene-environmental interactions with a large sample size with sufficient statistical power are recommended.

Neurological and neurophysiological examinations on workers with chronic poisoning by 2,3,7,8-TCDD: follow-up 35 years after exposure.

Between 1965 and 1968, about 350 workers were accidentally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a chemical plant, which was producing herbicides based on the trichlorophenoxyacetic acid. About 80 workers developed signs of poisoning. The estimated mean concentration of TCDD at the time of exposure was about 5000 pg/g of plasma fat. Only 15 subjects from the original cohort remained available for the recent follow-up in 2004. All were men, mean age 60 years. The mean current TCDD plasma concentration was 128 pg/g. Neurological examination revealed some CNS impairment in eight subjects. Signs of polyneuropathy were found in nine subjects, confirmed by NCV studies in three cases. Electroencephalography was abnormal in three cases; Visual-evoked potential in five cases. Acquired dyschromatopsia was detected in six patients. SPECT showed focal reduction of perfusion in various brain locations in all but one patient. Two neuropsychological variables and the frequency of abnormal neurophysiological tests in individual patients correlated with TCDD plasma level. The findings support the hypothesis that TCDD can damage the nervous system. In addition to a direct neurotoxic effect of TCDD, changes secondary to vasculopathy should be considered, in the pathophysiology of the damage, because of the high frequency of lipid metabolism disorders and their complications.

[Evaluation of the tumor extension before planned radical prostatectomy: a prospective study]. / Moznosti stanovení lokálního rozsahu karcinomu prostaty pred plánovanou radikální lécbou: prospektivní studie.

BACKGROUND: Study compares results of preoperative diagnostic methods with measurements of tumor extension in a specimen obtained by radical prostatectomy. METHODS AND RESULTS: One hundred forty-six patients with clinically identified cancer were enrolled in the study and subjected to radical prostatectomy. Each patient underwent transrectal sonography (TRUS), Power Doppler sonography with 3D reconstruction (3D-PDS), and the risk of the occurrence of locally advanced tumor was assessed using Partin tables. In subgroups of localized and locally advanced tumor, individual preoperative parameters were compared. ROC curves were generated for individual preoperative parameters and the area under the curve (AUC) was calculated. Multivariate logistic regression analysis was performed to determine independent predictors of extraprostatic tumor extension. A statistically significant difference between patients with localized and locally advanced tumor was observed in PSA levels (p < 0.014), PSA density (p < 0.004), DRE (p < 0.037), TRUS (p < 0.003), and 3D-PDS (p < 0.000). The highest AUC value was found for 3D-PDS 0.776, TRUS 0.670, and PSA density 0.639. According to multivariate analysis, independent preoperative predictors of extraprostatic tumor extension were PSA density, preoperative Gleason score 7, and 3D-PDS finding. CONCLUSIONS: Power Doppler sonography with 3D reconstruction represents the most reliable preoperative diagnostic tool in determining locally advanced tumor. Together with PSA density and the presence of aggressive tumor (Gleason score > or =7) in prostate biopsy, it is one of independent predictors of locally advanced prostate cancer.

Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations.

We used cytogenetic analysis to carry out a cohort study in which the major objective was to test the association between frequency of chromosomal aberrations and subsequent risk of cancer. In spite of the extensive use of the cytogenetic analysis of human peripheral blood lymphocytes in biomonitoring of exposure to various mutagens and carcinogens on an ecologic level, the long-term effects of an increased frequency of chromosomal aberrations in individuals are still uncertain. Few epidemiologic studies have addressed this issue, and a moderate risk of cancer in individuals with an elevated frequency of chromosomal aberrations has been observed. In the present study, we analyzed data on 8,962 cytogenetic tests and 3,973 subjects. We found a significant and strong association between the frequency of chromosomal aberrations and cancer incidence in a group of miners exposed to radon, where a 1% increase in frequency of chromosomal aberrations was followed by a 64% increase in risk of cancer (p < 0.000). In contrast, the collected data are inadequate for a critical evaluation of the association with exposure to other chemicals.

Biological monitoring of child lead exposure in the Czech Republic.

The area around the Pribram lead smelter has been recognized to be heavily contaminated by lead (Pb). In the early 1970s, several episodes of livestock lead intoxication were reported in this area; thereafter, several epidemiological and ecological studies focused on exposure of children. In contrast to earlier studies, the recent investigation (1992-1994) revealed significantly lower exposure to lead. From 1986-1990, recorded average blood lead levels were about 37.2 micrograms lead (Pb)/100 ml in an elementary school population living in a neighborhood close to the smelter (within 3 km of the plant). The present study, however, has found mean blood lead levels of 11.35 micrograms/100 ml (95% CI = 9.32; 13.82) among a comparable group of children. In addition to blood lead, tooth lead was used to assess exposure among children. Statistically significant differences (p < 0.05) were observed between the geometric mean tooth lead level of 6.44 micrograms Pb/g (n = 13; 95% CI = 3.95; 10.50) in the most contaminated zone and 1.43 micrograms Pb/g (n = 35; 95% CI = 1.11; 1.84) in zones farther away from the point source. Both biomarkers, blood and tooth lead levels, reflect a similar pattern of lead exposure in children. This study has attempted a quantitative assessment of risk factors associated with elevated lead exposure in the Czech Republic. Content of lead in soil, residential distance from the smelter, consumption of locally grown vegetables or fruits, drinking water from local wells, the mother's educational level, cigarette consumption among family members, and the number of children in the family were factors positively related (p < 0.05) to blood lead levels. The resulting blood lead level was found to be inversely proportional to the child's age.

Occupational exposure to carcinogens in Estonia, Latvia, Lithuania and the Czech Republic in 1997.

OBJECTIVES: The aim of the study was to estimate the numbers of workers exposed to carcinogens in Estonia, Latvia, Lithuania, and the Czech Republic. METHODS: CAREX is an international information system on occupational exposure to 139 known and suspected carcinogens. It provides exposure data and estimates of the numbers of exposed workers by country, carcinogen, and industry. The CAREX method, which has been previously applied in the member states of the European Union, was applied in the present study to the exposure situation in Estonia, Latvia, Lithuania, and the Czech Republic in 1997. The preliminary estimates generated by CAREX were reviewed and revised by national experts mainly for asbestos, benzene, and lead, which were of special interest for this project. RESULTS: The numbers of workers exposed to carcinogens covered by CAREX in 1997 were about 180,000 (29% of employed persons) in Estonia, 260,000 (28% of employed persons) in Latvia, 470,000 (28% of employed persons) in Lithuania, and 1,400,000 (28% of employed persons) in the Czech Republic. The most common exposures were solar radiation (7-13% exposed at least 75% of the worktime), environmental tobacco smoke (4-5% exposed at least 75% of the worktime), wood dust (3-5% exposed), crystalline silica (2-3% exposed), diesel exhaust (2-3% exposed), radon and its decay products (2% exposed), benzene (0.9-1.7% exposed), and lead and inorganic lead compounds (0.8-1.4% exposed). Exposure to asbestos was slightly less prevalent (0.3-1.1% exposed). CONCLUSIONS: These preliminary results indicate that a substantial proportion of the workers in the studied countries were exposed to carcinogens.

Biomonitoring of lead exposure in the Czech Republic.

The systematic and long-term efforts to protect the environment may be successful also in the country in the period of transition from centrally planned to free market economies. The basic requirement is to disseminate reliable information on the exposure levels and expected health effects. The need for high quality information underscores the importance of the quality assurance and quality control systems in the context of good laboratory as well as epidemiologic practices. Each monitoring study should be planned in the way facilitating its use for the evaluation of long-term trends. Besides scientific issues, the communication of risks is of crucial importance. According to our experience, only an involvement of formal as well as informal local authorities and co-operation between all relevant stakeholders can ensure the success.