Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis

被引:46
作者
Krajinovic, M
Costea, I
Primeau, M
Dulucq, S
Moghrabi, A
机构
[1] Ctr Hosp Univ Mere Enfant, Hop St Justine, Ctr Rech, Montreal, PQ H3T 1C5, Canada
[2] Univ Montreal, Dept Pediat, Montreal, PQ H3C 3J7, Canada
[3] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada
基金
加拿大健康研究院;
关键词
methotrexate; TS; multiple polymorphisms; haplotype; ALL; outcome;
D O I
10.1038/sj.tpj.6500332
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Thymidylate synthase (TS) is an essential enzyme in proliferating cells and an important target for several chemotherapeutics. Several TS gene polymorphisms correlate with variable TS expression: a double (2R) and triple (3R) 28-bp repeat element, a G to C substitution of the 3R allele and a 6 bp variation in 3'UTR. We have previously shown that childhood acute lymphoblastic leukemia ( ALL) patients who are homozygous for the 3R allele had reduced event-free survival (EFS) probabilities. Here, we analyzed all three polymorphisms in an extended group of ALL patients ( n = 259). The effect of the 3R homozygosity on ALL outcome was confirmed ( P = 0.006), whereas 6 bp polymorphism did not influence EFS when analyzed separately. No significant difference among 3R3R genotype subgroups, as defined by a G to C substitution, was observed. The haplotype analysis revealed the higher frequency of the 3RC/6 bp+ haplotype ( P = 0.04) and the protective role of the 2R/6b p - (P = 0.04). Consequently, homozygosity for the 6 bp - allele appeared to reduce an event-predisposing effect of 3R variant. Although of importance for translation into the clinical practice, these findings need confirmation in larger studies.
引用
收藏
页码:374 / 380
页数:7
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