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Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis

The Pharmacogenomics Journal volume 5, pages 374–380 (2005)Cite this article

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.

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Abbreviations

ALL:

acute lymphoblastic leukemia

ASO:

allele specific oligonucleotide

DFS:

disease free survival

dTMP:

deoxythymidine monophosphate

dUMP:

deoxyuridine monophosphate

EFS:

event free survival

5–FU:

5-fluorouracil

MTX:

methotrexate

MTX (Glu)n:

MTX polyglutamates

OS:

overall survival

2R:

double repeat

3R:

triple repeat

RA:

rheumatoid arthritis

TS:

thymidylate synthase

USF:

upstream stimulatory factor

WBC:

white blood cell

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Acknowledgements

We are indebted to all patients and their parents who consented to participate in this study. We are grateful to our colleagues Damian Labuda and Daniel Sinnett for discussion and biological material, Mark Bernstein for facilitating access to clinical data and Eef Harmsen for critical reading of the manuscript. MK is scholar of the Fonds de la Recherche en Santé du Québec. The Canadian Institutes of Health Research, Leukemia Research Fund of Canada and Centre de Recherche de l’Hôpital Sainte-Justine supported this study.

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Authors and Affiliations

  1. Centre de Recherche, Hôpital Sainte-Justine, Centre Hospitalier Universitaire Mère-Enfant, Montréal, Québec, Canada

    M Krajinovic, I Costea, M Primeau, S Dulucq & A Moghrabi

  2. Département de Pédiatrie, Université de Montréal, Montréal, Québec, Canada

    M Krajinovic & A Moghrabi

  3. Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada

    M Krajinovic

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  1. M Krajinovic
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  2. I Costea
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  3. M Primeau
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  4. S Dulucq
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Corresponding author

Correspondence to M Krajinovic.

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None declared.

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Krajinovic, M., Costea, I., Primeau, M. et al. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J 5, 374–380 (2005). https://doi.org/10.1038/sj.tpj.6500332

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