Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele.
Thymidylate synthase (TS) activity is an important determinant of response to chemotherapy with fluoropyrimidine prodrugs and its expression is largely determined by the number of functional upstream stimulatory factor (USF) E-box consensus elements present in the 5'regulatory region of the TYMS gene. Two known polymorphisms in this area, a variable number of tandem repeat (VNTR) consisting of 2 or 3 repeats (2R/3R) of a 28-bp sequence and a further G > C single nucleotide substitution within the second repeat of the 3R, result in genotypes with between 2 and 4 functional repeats in most humans. Here, we identify a further G > C SNP in the first repeat of the TYMS 2R allele, which effectively abolishes the only functional USF protein binding site in this promoter. The frequency of the new allele was found to be 4.2% (95% CI = 1.4-9.6%), accounting for 8.8% (95% CI = 2.9-19.3%) of all 2R alleles in our patient cohort. Thus, we observed that the lowest number of inherited functional binding sites is 1 instead of 2 as previously thought, and could potentially be 0 in a homozygous individual. This would severely decrease TS expression and may have implications for predicting efficacy and toxicity of therapy with commonly used fluorouracil-based therapy regimes.
Lincz
Lisa F
LF
Hunter Haematology Research Group, Newcastle Mater Misericordiae Hospital, Waratah, NSW 2298, Australia.
Scorgie
Fiona E
FE
Garg
Madhu B
MB
Ackland
Stephen P
SP
D000483:Alleles; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D013940:Thymidylate Synthase / Q000235:genetics*
D013940:Thymidylate Synthase