A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels

Michael V Mandola, Jan Stoehlmacher, Wu Zhang, Susan Groshen, Mimi C Yu, Syma Iqbal, Heinz-Josef Lenz, Robert D Ladner

Research output: Contribution to journalArticlepeer-review

278 Citations (Scopus)

Abstract

OBJECTIVE: A 6 bp deletion polymorphism in the thymidylate synthase (TS) gene was investigated in order to determine its function.

METHODS: A luciferase system was used to investigate the function of the 6 bp/1494 polymorphism in vitro. A group of 43 patients with colorectal carcinoma were evaluated for the 6 bp/1494 polymorphism and for intratumoral TS mRNA levels in vivo.

RESULTS: The 3'UTR of TS containing the +6 bp polymorphism resulted in an approximate 35% decrease in luciferase activity and mRNA levels, while the TS-3'UTR bearing the -6 bp deletion resulted in an approximate 70% decrease in luciferase activity and mRNA levels. The TS-3'UTR construct containing the -6 bp/1494 deletion also had a higher rate of message degradation compared to the +6 bp/1494 construct. Individuals homozygous for the insertion (+6 bp/+6 bp) had significantly higher TS mRNA levels compared to individuals that were homozygous for the deletion (-6 bp/-6 bp) (P < 0.007). We determined the frequency of the -6 bp/1494 deletion polymorphism to be 41% in non-Hispanic whites, 26% in Hispanic whites, 52% in African-Americans and 76% in Singapore Chinese.

CONCLUSIONS: These results suggest that the -6 bp/1494 deletion polymorphism in the 3'UTR of TS is associated with decreased mRNA stability in vitro and lower intratumoral TS expression in vivo. Further, the 6 bp/1494 polymorphism varies greatly within different ethnic populations and is in linkage disequilibrium with the TS 5' tandem repeat enhancer polymorphism. Taken together, these data suggest that the 6 bp/1494 polymorphism may be a useful screening tool in predicting TS mRNA expression.

Original languageEnglish
Pages (from-to)319-27
Number of pages9
JournalPharmacogenetics
Volume14
Issue number5
Publication statusPublished - May 2004

Keywords

  • 3' Untranslated Regions
  • Base Sequence
  • Cell Line
  • Colorectal Neoplasms
  • DNA Primers
  • Enhancer Elements, Genetic
  • Ethnic Groups
  • Humans
  • Polymorphism, Genetic
  • RNA, Messenger
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Deletion
  • Tandem Repeat Sequences
  • Thymidylate Synthase
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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