Fourteen Novel Genetic Variations and Haplotype Structures of the TYMS Gene Encoding Human Thymidylate Synthase (TS)

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  • KIM Su-Ryang
    Project Team for Pharmacogenetics, National Institute of Health Sciences
  • OZAWA Shogo
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Pharmacology, National Institute of Health Sciences
  • SAITO Yoshiro
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences
  • KUROSE Kouichi
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Medicinal Safety Science, National Institute of Health Sciences
  • KANIWA Nahoko
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Medicinal Safety Science, National Institute of Health Sciences
  • KAMATANI Naoyuki
    Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University
  • HAMAGUCHI Tetsuya
    Gastrointestinal Oncology Division, National Cancer Center Hospital
  • SHIRAO Kuniaki
    Gastrointestinal Oncology Division, National Cancer Center Hospital
  • MUTO Manabu
    Gastrointestinal Oncology Division, National Cancer Center Hospital East
  • OHTSU Atsushi
    Gastrointestinal Oncology Division, National Cancer Center Hospital East Division of Digestive Endoscopy, National Cancer Center Hospital East
  • YOSHIDA Teruhiko
    Genetics Division, National Cancer Center Research Institute
  • MATSUMURA Yasuhiro
    Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East
  • SAIJO Nagahiro
    Deputy Director, National Cancer Center Hospital East
  • SAWADA Jun-ichi
    Project Team for Pharmacogenetics, National Institute of Health Sciences Division of Biochemistry and Immunochemistry, National Institute of Health Sciences

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Abstract

  Forty genetic variations including 14 novel ones were found in the human TYMS gene, which encodes thymidylate synthase, in 263 Japanese cancer patients who received 5-fluorouracil (FU)-based chemotherapy. Three novel variations were located within the 28-bp tandem repeat sequence in the 5′-untranslated region (UTR) and were designated 5Rc, 3Rc-ins and 4Rc. Allele frequencies were 0.021 for 5Rc, 0.006 for 3Rc-ins and 0.002 for 4Rc. Other novel variations included -133G>C and -125G>C in the 5′-UTR; IVS1-278G>A, IVS2-68C>T, IVS2-23T>C, IVS4+122_+123insATTG, IVS4-141G>A, IVS5-100A>T and IVS6-111G>A in the introns; and 1244(*302)A>G and 1264(*322)G>A in the 3′-UTR. The allele frequencies were 0.34 for IVS4+122_+123insATTG, 0.042 for -133G>C, 0.011 for IVS4-141G>A, 0.006 for -125G>C, 0.004 for IVS1-278G>A, IVS2-68C>T, 1244(*302)A>G and 1264(*322)G>A, and 0.002 for IVS2-23T>C, IVS5-100A>T and IVS6-111G>A. Using the detected polymorphisms, linkage disequilibrium (LD) analysis was performed, which divided the TYMS gene into three LD blocks. The 28-bp tandem repeat sequence in the 5′-UTR was assigned as Block 2 with a total of 7 alleles. In Blocks 1 and 3, 7 and 19 haplotypes were determined/inferred, respectively. Our findings provide fundamental and useful information for genotyping TYMS in the Japanese and probably other Asian populations.<br>

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