Cancer esearch ention and Epidemiology upational Trichloroethylene Exposure and Renal cinoma Risk : Evidence of Genetic Susceptibility by R uctive Metabolism Gene Variants

acrjourna hloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predomy through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine β-lyase 1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically ed to assess risk associated with occupational exposure to TCE through analysis of detailed job histoll jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequenintensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; onfidence interval (95% CI), 1.04–2.54]. Exposure-response trends were observed among subjects above low the median exposure [average intensity (OR = 1.38; 95% CI, 0.81–2.35; OR = 2.34; 95% CI, 1.05–5.21; = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 (active genotype; OR = 1.88; 95% CI, 1.06–3.33) but not among subjects with two deleted alleles enotype; OR = 0.93; 95% CI, 0.35–2.44; Pinteraction = 0.18). Similar associations for all exposure metrics ing average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79–3.10; OR = 5% CI, 1.01–7.58; Ptrend = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% 7–5.04; Ptrend = 1.00; Pinteraction = 0.34). Further evidence of heterogeneity was seen among TCE-exposed ts with ≥1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, 043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associith increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are ated w important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans. Cancer Res; 70(16); 6527–36. ©2010 AACR.

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