Association of CYP2C9 genotypes leading to high enzyme activity and colorectal cancer risk

CYP2C9 enzyme activity is involved in the metabolism of substances related to colorectal cancer, and it is functionally linked to a genetic polymorphi sm. Two allelic variants of the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, differ from wild-type CYP2C9*1 by single amino acid substitutions. These mu tated alleles encode enzymes with altered properties that are associated wi th impaired metabolism. The present study evaluates the impact of CYP2C9 ge notypes leading to high enzyme activity on colorectal cancer risk. For this , the frequency of allelic variants of the CYP2C9 gene was analysed in geno mic DNA from 129 patients with colorectal cancer and in 150 healthy control s. Patients with colorectal cancer showed a statistically significant incre ase in the frequency of genotypes homozygous for the active CYP2C9*1 gene, as compared with healthy individuals. Such a high frequency is more signifi cant among patients with cancer in proximal segments of the colon (P < 0.02 5; odds ratio 2.36 95% CI 1.18-4.72), and decreases in more distal tumour l ocations. We conclude that CYP2C9 polymorphism can be considered as a secon dary risk factor for colorectal cancer in the studied population: those ind ividuals with genotypes leading to high enzyme activity were at increased r isk. The association of the CYP2C9 polymorphism to colorectal cancer risk c ould be related to CYP2C9-mediated metabolic activation of polycyclic aroma tic hydrocarbons and heterocyclic aromatic amines. In addition, the key rol e of CYP2C9 in the metabolic inactivation of non-steroidal antiinflammatory drugs could diminish the protective effect of these drugs against colorect al cancer.