Occupational trichloroethylene exposure and renal carcinoma risk: evidence of genetic susceptibility by reductive metabolism gene variants.
Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine beta-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P(trend) = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P(interaction) = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P(trend) = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P(trend) = 1.00; P(interaction) = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with >or=1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans.
Moore
Lee E
LE
Division of Cancer Epidemiology and Genetics, NIH, National Cancer Institute, NIH, Bethesda, Maryland 20852, USA. moorele@mail.nih.gov
Boffetta
Paolo
P
Karami
Sara
S
Brennan
Paul
P
Stewart
Patricia S
PS
Hung
Rayjean
R
Zaridze
David
D
Matveev
Vsevolod
V
Janout
Vladimir
V
Kollarova
Helena
H
Bencko
Vladimir
V
Navratilova
Marie
M
Szeszenia-Dabrowska
Neonila
N
Mates
Dana
D
Gromiec
Jan
J
Holcatova
Ivana
I
Merino
Maria
M
Chanock
Stephen
S
Chow
Wong-Ho
WH
Rothman
Nathaniel
N
D013437:Carbon-Sulfur Lyases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D003043:Cocarcinogenesis; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D016273:Occupational Exposure / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D014241:Trichloroethylene / Q000506:poisoning*
D014241:Trichloroethylene; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase