Document Detail


A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels.
MedLine Citation:
PMID:  15115918     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Michael V Mandola; Jan Stoehlmacher; Wu Zhang; Susan Groshen; Mimi C Yu; Syma Iqbal; Heinz-Josef Lenz; Robert D Ladner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Pharmacogenetics     Volume:  14     ISSN:  0960-314X     ISO Abbreviation:  Pharmacogenetics     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-04-29     Completed Date:  2004-12-06     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9211735     Medline TA:  Pharmacogenetics     Country:  England    
Other Details:
Languages:  eng     Pagination:  319-27     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Lippincott Williams & Wilkins
Affiliation:
Department of Molecular Biology, The University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey 08084, USA.
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MeSH Terms
Descriptor/Qualifier:
3' Untranslated Regions
Base Sequence
Cell Line
Colorectal Neoplasms / enzymology*
DNA Primers
Enhancer Elements, Genetic
Ethnic Groups / genetics
Humans
Polymorphism, Genetic*
RNA, Messenger / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Sequence Deletion
Tandem Repeat Sequences
Thymidylate Synthase / genetics*
Grant Support
ID/Acronym/Agency:
5 P30 CA14089-27/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/3' Untranslated Regions; 0/DNA Primers; 0/RNA, Messenger; EC 2.1.1.45/Thymidylate Synthase

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