title: Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis.
abstract: 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.
authors.affiliation: Centre de Recherche, Hôpital Sainte-Justine, Centre Hospitalier Universitaire Mère-Enfant, 3175 Côte-Sainte-Catherine, Montréal, Québec, Canada H3T 1C5. maja.krajinovic@umontreal.ca
authors.forename: M
authors.initials: M
authors.lastname: Krajinovic
authors.forename: I
authors.initials: I
authors.lastname: Costea
authors.forename: M
authors.initials: M
authors.lastname: Primeau
authors.forename: S
authors.initials: S
authors.lastname: Dulucq
authors.forename: A
authors.initials: A
authors.lastname: Moghrabi
mesh_terms: D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D010597:Pharmacogenetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D013940:Thymidylate Synthase