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

被引:253
作者
Mandola, MV
Stoehlmacher, J
Zhang, W
Groshen, S
Yu, MC
Iqbal, S
Lenz, HJ
Ladner, RD
机构
[1] Univ Med & Dent New Jersey, Sch Osteopath Med, Dept Mol Biol, Stratford, NJ 08084 USA
[2] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Div Oncol, Los Angeles, CA 90033 USA
[3] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA
[4] Univ Hamburg, Med Ctr, Dept Internal Med 2, D-20246 Hamburg, Germany
来源
PHARMACOGENETICS | 2004年 / 14卷 / 05期
关键词
colorectal carcinoma; 3 ' UTR; 5-FU; polymorphism; thymidylate synthase;
D O I
10.1097/00008571-200405000-00007
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 a similar to35% decrease in luciferase activity and mRNA levels, while the TS-3'UTR bearing the -6 bp deletion resulted in a similar to70% 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. (C) 2004 Lippincott Williams Wilkins.
引用
收藏
页码:319 / 327
页数:9
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