Association of C3435T and G2677T/A polymorphisms of multidrug resistance (MDR1) gene with colorectal cancer risk

Abstract

The human multidrug-resistance (MDR1) gene encodes an integral cell membrane protein, P-glycoprotein (PGP), which generates the ATP-dependent cellular transport of substances. The activation of responsive elements in MDR1 gene promoter occurs in earlier colorectal carcinogenesis. In combination with cell proliferative activities of c-myc and cyclin D1, MDR1 may initiate colorectal tumorogenesis by suppressing cell death pathways. The failure of correct cell death mechanisms disturbs the epithelium homeostasis and may induce tumorogenesis. We have studied if the hereditarily determined activity of MDR1 could modulate the risk of developing of colorectal cancer and have investigated genetic variant 3435C>T in exon 26 and triple polymorphism 2677G>T/A in exon 21 in a group of 289 colorectal cancer patients and sex- and age-matched controls. Genotyping was performed by PCR/RFLP and Real-Time PCR assays. Homozygous carriers of 3435C allele had 1.65 (95% C. I., 1.1-2.5) higher risk (p=0.01) than carriers of 3435T allele. Presence of at least one 3435T protects significantly against colorectal cancer. Similar effect was shown for the mutation in exon 21. Carries of one 2677T allele had a lower risk of colorectal cancer (OR=0.65, 95% C. I., 0.45–0.94, p=0.02). The 2677G>T/A polymorphism and the 3435C>T polymorphism displayed tight allelic association (p<0.001). Our data suggest that carries of active MDR1 alleles are at the higher risk to develop the colorectal cancer. Clinical Pharmacology & Therapeutics (2004) 75, P17–P17; doi: 10.1016/j.clpt.2003.11.065