Schaerer Dominic, Froehlich Tanja K, Hamzic Seid, Offer Steven M, Diasio Robert B, Joerger Markus, Amstutz Ursula, Largiadèr Carlo R
University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
J Pers Med. 2020 Oct 19;10(4):181. doi: 10.3390/jpm10040181.
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 (). 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.
抑制胸苷酸合成酶（TS）是5-氟尿嘧啶（5FU）化疗的主要作用方式。TS表达受位于TS基因上游的TS增强子区域（TSER）中可变数量串联重复序列的调控。有人认为TSER的变异性会导致5FU诱导的不良事件。然而，由于高多态性以及定义基因型时的模糊性，确切的基因关联在很大程度上仍不明确。为了评估毒性关联，我们对629例接受5FU治疗的癌症患者的TSER进行了测序。在鉴定出的13个等位基因中，使用当前的TSER命名法几乎无法明确命名。我们设计了一种简洁明了的TSER等位基因系统命名方法，该方法涵盖了所有已知变体。将这个全面的命名系统应用于我们的数据后，我们证明TSER中上游刺激因子（USF1）结合位点的数量与5FU治疗中的胃肠道毒性显著相关。
