Extreme environmental pollution such as that found in the highly industrialized Silesian region of Poland has been associated with increased risk of cancer and adverse reproductive outcomes. Among the most prevalent carcinogenic and mutagenic air pollutants in Silesia are the polycyclic aromatic hydrocarbons (PAH) which are largely produced by industrial and residential combustion of coal. Molecular epidemiology aims to prevent disease by using biological markers to identify risks well before clinical onset to allow effective intervention. Here, we use a battery of biological markers to measure molecular and genetic damage in peripheral blood samples from residents of Silesia and from persons living in a rural, less polluted area of Poland. The results show that their exposure to environmental pollution is associated with significant increases in carcinogen-DNA adducts (PAH-DNA and aromatic adducts), in sister chromatid exchange including high-frequency cells, and in chromosomal aberrations as well as a doubling in the frequency of ras oncogene overexpression. We found that aromatic adducts on DNA were significantly correlated with chromosomal mutation, providing us with a molecular link between environmental exposure and a genetic alteration relevant to cancer and reproductive risk.

Apoptosis is important for targeting cancer cells for destruction. Various single-nucleotide polymorphisms (SNPs) in apoptotic genes have been associated with increased risks in lung cancer, particularly FAS 21377 G>A (rs2234767), FASLG 2844 C>T (rs763110), IL1B 13954 C>T Phe105Phe (rs1143634) and BAT3 Ser625Pro (rs1052486). We studied the association of these SNPs with non-small cell lung cancer (NSCLC) in a large case-control study (N 5 4263: 2644 cases and 1619 controls). No associations with NSCLC were observed in the main effects analysis for all four SNPs, adjusting for age, gender, smoking status, pack-years and years since smoking cessation. In subjects under age 60, for FASLG 2844 C>T polymorphism, CT compared with the CC genotype, was significantly associated with increased risk of NSCLC, adjusted odds ratio (aOR) 5 1.58 (1.22, 2.05), P 5 0.0006 and TTaOR 5 1.45 (1.01, 2.04), P 5 0.04. In contrast, for those over age 60, the CT aOR 5 0.91 (0.73, 1.13), P 5 0.37 and TT aOR 5 0.86 (0.64, 1.16), P 5 0.32. The P-value for the age-genotype interaction was 0.004. For the IL1B 13954 C>T polymorphism, compared with the CC genotype, TT showed significant associations in former smokers and in men but tests of interaction were not significant (P smoking 5 0.24, P gender 5 0.17). No interactions were observed for FAS 21377 G>A and BAT3 Ser625Pro polymorphisms. Our findings indicate that age and smoking may modify the association of the FASLG 2844 and IL1B 1 3954 SNPs with the risk of NSCLC.

Nonsteroidal antiinflammatory drugs (NSAIDs) use, particularly aspirin, may lower the risk of several cancers, including bladder. NSAIDs may reduce development of bladder tumors by decreasing inflammation, inhibiting cycloxygenase-2, inhibiting proliferation and inducing apoptosis of cancer cells. However, acetaminophen, a major metabolite of phenacetin, may be positively associated with bladder cancer risk. Results from case-control studies on NSAIDs and acetaminophen use and bladder cancer risk are inconsistent. We investigated the association between NSAID and acetaminophen use and bladder cancer risk in a large cohort of US males. Among 49,448 men in the Health Professionals FollowUp Study, 607 bladder cancer cases were confirmed during 18 years of follow-up. Relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models. Multivariate RR were adjusted for age, current smoking status, pack years, geographic region and fluid intake. No significant associations were observed for regular aspirin ( 2 tablets per week), (RR 5 0.99, 95% CI 0.83-1.18), ibuprofen (RR 5 1.11, 95% CI 0.81-1.54), acetaminophen (RR 5 0.96, 95% CI 0.67-1.39) or total NSAID use (not including acetaminophen; RR 5 1.01, 95% CI 0.85-1.20) and bladder cancer risk compared with nonuse. Consistent use (over 6 years) of aspirin, ibuprofen, acetaminophen and total NSAIDs, compared to nonuse, was not associated with bladder cancer risk. No association was observed between aspirin frequency and dose and bladder cancer risk. We observed no effect-modification by smoking, age or fluid intake. Our results suggest that regular NSAID or acetaminophen use has no substantial impact on bladder cancer risk among men. ' 2007 Wiley-Liss, Inc.Key words: bladder cancer; NSAID use; epidemiology; cohort In the US, bladder cancer is the fourth most common cause of cancer among men and the ninth most common cause of cancer death among men. 1 Bladder cancer is approximately 2-4 times more common in males compared to females 2,3 and there is an approximately twofold higher risk among Caucasian compared to African American men. 2 Cigarette smoking, 4,5 occupational exposures to aromatic amines 6-8 and schistosomal infections 9,10 have been associated with risk of bladder cancer. Other environmental factors, including selenium intake, 8 chlorination by-products 11,12 and low dose arsenic levels in water sources, 13,14 have also been associated with bladder cancer, but are less well-established.Epidemiologic evidence suggests that use of nonsteroidal antiinflammatory drugs (NSAIDs), particularly aspirin, may lower the risk of several cancers, 15-20 including bladder cancer. 21 Several epidemiologic studies on urinary tract infections, 22,23 indwelling catheters, 24 bladder stones 25 and schistosomiasis 26 all support a role for inflammation in bladder carcinogenesis. In addition, recent animal and cell line studies show that risk of bladder cancer may be associated with inflammation and upregulation of cycloxygenase-2 (COX-2). 27...

Mutations in ras oncogenes and expression of their encoded p21 protein products are believed to play an important role in carcinogenesis in humans. Detection of mutant p21 proteins in serum may be a useful molecular epidemiologic biomarker with which to study this process, and workers with heavy exposure to vinyl chloride (VC) represent a model population for such study. We studied the occurrence of a specific ras mutation (Asp 13 c-Ki-ras) by oligonucleotide hybridization and the expression of the corresponding p21 protein in tumor tissue and serum by immunohistochemistry and immunoblotting with monoclonal antibodies in five individuals with heavy exposure to VC and resultant angiosarcomas of the liver (ASL). Four of five (80 percent) of the cases of ASL were found to contain the mutation and to express the corresponding mutant protein in their tumor tissue and serum. Serum expression of the mutant protein also was examined in nine VC-exposed workers with liver angiomas and 45 VC-exposed workers with no evidence of liver neoplasia; eight of nine (89 percent) of the former and 22 of 45 (49 percent) of the latter were also positive for the mutant p21 in their serum. However, serum immunoblotting results for 28 age-gender-race matched, unexposed controls were all negative. Stratification by years of VC exposure showed a significant linear trend (P < 10(-5)) for the occurrence of the serum mutant p21 protein with increasing duration of exposure. These results suggest that detection of serum mutant p21 protein can be a valid surrogate for ras gene expression at the tissue level.(ABSTRACT TRUNCATED AT 250 WORDS)