Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: A study of polymorphic human xenobiotic-metabolizing enzymes

The steady increase in sporadic renal cell carcinoma (RCC) observed in indu strialized countries supports the notion that certain carcinogens present i n the environment (tobacco smoke, drugs, pollutants, and dietary constituen ts) may affect the occurrence of RCC. Many of the enzymes dealing with such environmental factors are polymorphic and mag, therefore, confer variable susceptibility to RCC. This case-control study was designed to test for an association between genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of sporadic RCC. Genomic DNA was obtained from 173 patients with RCC and 211 controls of Caucasian origin. We used PCR-RFLP to investigate polymorphism for the most common alleles at two cytochrome-P45 0 mono-oxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase ( HQO1), three glutathione S-transferases (GSTM1, GSTT1, and GSTP1), and one N-acetyltransferase (NAT2) loci. The CYP1A1 (m) "variant" genotype, which c ontains at least one copy of the CYP1A1 variant alleles, was found to be as sociated with a 2.1-fold [95% confidence interval (CI), 1.1-3.9] increase i n the risk of RCC. There was also a higher risk of RCC for subjects with th e CYP1A1 (m) variant genotype combined with any of the following genotypes: GSTT1 (+) "active'' [odds ratio (OR), 2.3; 95% CI, 1.2-4.5], GSTP1 (m) var iant (OR, 2.4; 95%, CI, 1.0-5.4), or NAT2 (-) "slow acetylator" (OR, 2.5; 9 5% CI, 1.1-5.5). A significant association was also found for the GST,MI (- ) "null" and GSTP1 (m) genotypes combined with either NAT2 (-) (OR, 2.6; 95 % CI, 1.2-5.8) or CYP1A1 (m) (OR, 3.5; 95% CI, 1.1-11.2). The CYP2D6 (-) "p oor metabolizer' and the NQO1 (-) "defective" genotypes were not clearly as sociated with a higher risk of RCC. Our data demonstrate for the first time a significant association between a group of pharmacogenetic polymorphisms and RCC risk. These positive findings suggest that interindividual variati on in the metabolic pathways involved in the functionalization and detoxifi cation of specific xenobiotics is an important susceptibility factor for RC C in Caucasians.