Thymidylate synthase gene polymorphisms effecting 5-FU response in breast cancer patients

Abstract

Our study supports the Drug-Gene Interaction principle, where patients experience adverse drug reactions (ADRs) due to genetic predisposition or due to single nucleotide polymorphisms (SNPs) in drug metabolizing genes. The target enzyme for 5- Fluorouracil is thymidylate synthase (TYMS) this enzyme is also involved in folate metabolism. We determined the frequencies of polymorphisms in drug metabolizing enzyme like TYMS and correlated the drug response in 140 breast cancer patients compared to 150 controls, using PCR and RFLP method. In our results the TYMS1494del polymorphism was statistically significant; allele frequencies for 6bp deletion and 6bp insertion were 0.85 and 0.15 in BC (Breast Cancer) patients compared with 0.95 and 0.04 in controls. The enhancer region 2R/3R heterozygote genotypes were found to be not significant for BC risk. In this study combined genotypes showed 2 fold increased risk of BC. Frequency distribution of 2R and 3R allele among BC patients was 0.85 and 0.15 and 0.95 and 0.04 in controls respectively. Correlation analysis of TYMS enhancer region polymorphisms with drug response suggested that the response was poor in BC patients with 2R/3R and 2R/2R genotypes, but patients with poor response were fewer in number, that this gene may be important in drug response. Genetic screening of the drug metabolizing enzyme like TYMS for the presence of polymorphisms in breast cancer patients will become increasingly useful in individualizing drug therapy.