A Novel Nomenclature for Repeat Motifs in the Thymidylate Synthase Enhancer Region and Its Relevance for Pharmacogenetic Studies

Journal of Personalized Medicine

Markus Joerger¹  Robert B. Diasio²  Steven M. Offer²  Tanja K. Froehlich³  Seid Hamzic³  Carlo R. Largiadèr³  Ursula Amstutz³  Dominic Schaerer³ 

[1] Department of Medical Oncology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland;Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA;University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;

关键词: 5-fluorouracil;    capecitabine;    fluoropyrimidine;    thymidylate synthase;    thymidylate synthase enhancer region;    upstream stimulatory factor 1;   

DOI  :  10.3390/jpm10040181

来源: DOAJ

【 摘 要 】

Inhibition of thymidylate synthase (TS) is the primary mode of action for 5-fluorouracil (5FU) chemotherapy. TS expression is modulated by a variable number of tandem repeats in the TS enhancer region (TSER) located upstream of the TS gene (TYMS). Variability in the TSER has been suggested to contribute to 5FU-induced adverse events. However, the precise genetic associations remain largely undefined due to high polymorphism and ambiguity in defining genotypes. To assess toxicity associations, we sequenced the TSER in 629 cancer patients treated with 5FU. Of the 13 alleles identified, few could be unambiguously named using current TSER-nomenclature. We devised a concise and unambiguous systematic naming approach for TSER-alleles that encompasses all known variants. After applying this comprehensive naming system to our data, we demonstrated that the number of upstream stimulatory factor (USF1-)binding sites in the TSER was significantly associated with gastrointestinal toxicity in 5FU treatment.

【 授权许可】

Unknown