Analysis of Polymorphisms and Haplotype Structure of the Human Thymidylate Synthase Genetic Region: A Tool for Pharmacogenetic Studies

Abstract

5-fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5′-untranslated region (5′-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

Gene expression profiling reveals upregulated FUT1 and MYBPC1 in children with pancreaticobiliary maljunction

“…TYMS is located on chromosome 18p11.32, and is composed of six introns with sizes ranging from 507 to 6271 bp and seven exons with sizes ranging from 72 to 250 bp (16 –18). TYMS encodes for thymidylate synthase (TS), an enzyme indispensable for DNA synthesis and repair (19).…”

Germline and somatic genetic predictors of pathological response in neoadjuvant settings of rectal and esophageal cancers: systematic review and meta-analysis

“…The number of tandem repeats affects TYMS activity levels: TYMS mRNA with the threerepeat sequence has greater translational efficiency than that with the two-repeat sequence. 25,26 TYMS sequencing has shown nine SNP haplotypes accounting for 490% of the studied population, 27 but nowadays only VNTR (rs34743033) is best characterized as functional. The results of our meta-analysis are in line with the results of a recent meta-analysis of TYMS VNTR association with chemotherapy response in colorectal cancer.…”

An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities

“…Enolase Superfamily member 1 (ENOSF1) has several isoforms, whilst one converts L-fuconate to 2-keto-3-deoxy-L-fuconate other isoforms seems to regulate thymidylate synthase (TS) at the transcript and protein level [ 13 ]. rs2612091 is in strong linkage disequilibrium (LD) with TYMS variants extensively studied in relation to 5-FU toxicity [ 14 , 15 ].…”