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.

Pharmacogenomics Influencing Drug-Gene Interactions Leading Towards Personalized Medicine

“…Our research, was to understand genes involved in pharmacogenomics, which seeks to identify the factors that influence responses to therapeutic agents, in cancer patients compared to healthy age matched volunteers using methods such as PCR, RFLP/ SSCP and SNP analysis by Sanger's sequencing [13][14][15][16][17][18][19]40] to identify SNP biomarkers. Genotyping methods are improving so rapidly that it will soon be simple to test for thousands of single-nucleotide polymorphisms in one assay.…”

“…The role of genes like CYPs, TS, MTHFR, SULT1A1, and DPD in cancers as seen in our studies, represents a test for ADR when the drug is administered and the proportion of people with a negative test who will not have an ADR, respectively [13][14][15][16][17][18][19]40]. These are among some of the first reports from India analyzing the association of polymorphisms in several drug metabolizing genes, showing the druggene interactions which are associated with various cancers.…”

“…We have studied genetic polymorphisms in several drug metabolizing genes [13][14][15][16][17][18][19], and how this information can be used by clinicians for determining drug doses or alternate chemotherapeutics. In the context of chemotherapeutic drugs, we have demonstrated that polymorphisms in genes encoding drug metabolizing enzymes influence and affect the clinical outcome [13,16,17,19].…”

“…In the context of chemotherapeutic drugs, we have demonstrated that polymorphisms in genes encoding drug metabolizing enzymes influence and affect the clinical outcome [13,16,17,19]. It was essential to examine the addition factors or parameters such as patients' demographics such as age, sex, hormones, and behavioral factors such as cigarette smoking, alcohol consumption, and nutritional status as these also have been found to influence the expression of phase I and II biotransformation genes [13][14][15][16][17][18][19]. This data was used to correlate the allele's verses drug toxicity.…”

“…This article outlines a wide spectrum of genes that interact with drug metabolizing enzymes with respect to various chemo-treatments (regimens) of cancer patients by studying and determining their genotypes from the biopsy samples-from our research such as breast cancer, head and neck cancer, hematological malignancies and lung cancer and correlates the mechanism by which these genetic variation influence treatment response [13][14][15][16][17][18][19][24][25][26]. Further during these investigations we have listed several biomarkers which are very important to determine before treatment.…”