Polymorphism of cytochrome P450 (CYP) genes and response to chemiotherapy in patients with colorectal cancer (CRC)

Abstract

Background: Genes coding for the cytochrome P450 (CYP) enzyme system implied in antineoplastic drug metabolism pathways are highly polymorphic. This may influence both carcinogen metabolism and drug pharmacodynamics modifying their therapeutic efficacy and side effects. Methods: We investigated the influence of genetic polymorphisms of CYP enzymes: rs1799853 (CYP2C9), rs35742686 (CYP2D), rs5030655 (CYP2D6/3), rs2740574 (CYP3A4/1) rs776746 (CYP3A5) on the response of chemotherapy and clinical outcomes, in a group of 56 patients affected by sporadic CRC, treated with the standard protocols. A total of 44 patients were in complete remission after treatment, 12 had persistence of the disease. Polymorphisms were typed using a competitive allele specific PCR assay (KASPar), developed by KBioscience. Statistical were analyzed using the χ2 test with Yates correction and Fisher's Exact Test. Significance was defined as p values <0.05. Results: No significant genetic contribute was observed for 4 of the 5 SNPs tested. A significant different genetic distribution between patients in complete remission after treatment and those of symptomatic patients was observed for the polymorphism C→T (rs1799853) responsible of an Arg144Cys change in CYP2C9 and associated with reduced enzyme activity (p=0.031, O.R.= 4.760, 95% C. I.: 1.237 to 18.311). Conclusions: These results suggest that rs1799853 is a functionaly relevant SNP of CYP2C9 that may influence the efficacy of therapy. Thus, pharmacogenetic biomarkers have the potential of optimizing chemotherapy for individual patients