analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region a tool for pharmacogenetic studies分析人类thymidylate合成酶基因的多态性和单体型结构地区药理遗传学研究的工具.pdfVIP

Analysis of Polymorphisms and Haplotype Structure of the Human Thymidylate Synthase Genetic Region: A Tool for Pharmacogenetic Studies 1 1 2 1,2 3 Soma Ghosh , M. Zulfiquer Hossain , Michael Borges , Michael G. Goggins , Roxann G. Ingersoll , 1,2 1,2 1 James R. Eshleman , Alison P. Klein , Scott E. Kern * 1 Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America, 3 Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America 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 59-untranslated region (59-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 nucleo