Classification of thymidylate synthase gene enhancer region polymorphisms

Dear Sir, Gusella et al. and Lincz et al. have recently identified a new single nucleotide polymorphism in the enhancer region of the 2R allele of the thymidylate synthase gene (TYMS), consisting in a G>C base change at the 12th nucleotide of the first 28-bp repeat. This finding enlarges the number of possible TYMS allelic variants and calls for a revision of the present classification. Lincz et al. designated the new allele 2RCC to indicate the SNPs present in the first and second repeats of the 2R allele and in order to maintain consistency, they adopted this notation for the 3R alleles as well, so that the alleles formerly quoted in most literature as 3RG and 3RC became 3RGGC and RGCC, respectively. Since the latter structurebased nomenclature seemed to the authors themselves somewhat cumbersome and at risk of becoming more complex if similar SNPs would be identified in all TYMS alleles, at present consisting of 1–9 repeats, they proposed a new, simplified functional classification system, integrating the variable number of tandem repeat (VNTR) polymorphism with the new acquisitions regarding the allied G>C polymorphism, and based on the number of the E-box consensus elements for the upstream stimulatory factor-1 (USF-1). In fact, it was demonstrated that the G>C change abolishes the ability of the USF-1 to bind the E-box and to increase the TYMS transcriptional activity. Considering the allelic variants identified so far, the new functional notation ranges from 0 for a homozygous 2RCC to a maximum of 4 for a homozygous 3RGGC individual. However, the authors suggest that if a C>G SNP will be identified in the first repeat of the 3R allele, then the possibility of 6 putative functional repeats would exist (i.e., 3RGGG/ 3RGGG) and could be easily accommodated by this system.