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Polymorphisms in Genes Involved in the Corticosteroid Response and the Outcome of Childhood Acute Lymphoblastic Leukemia

  • Original Research Article
  • Published:
American Journal of Pharmacogenomics

Abstract

Background

Considerable variability in sensitivity to corticosteroids (CS) has been observed among individuals with regard to both the natural and synthetic compounds. The role of genetic polymorphisms in modulating CS function, and hence in disease susceptibility, has been extensively analyzed. Their impact on therapeutic response still remains to be explored. The role of cytochrome P450 (CYP) 3A4 in corticosteroid metabolism, and that of the glucocorticoid receptor (NR3C1) in regulation of responsive genes, renders CYP3A4 and NR3C1 polymorphisms as potential candidates for pharmacogenetic analysis.

Aim

The aim of the study was to analyze the role of these polymorphisms in the outcome of a disease treated with CS drugs.

Methods

Towards this aim we analyzed the CYP3A4–290A/G substitution and three NR3C1 polymorphisms (200G/A, 1220A/G and BclI RFLP) in 222 children with acute lymphoblastic leukemia (ALL) whose treatment protocols, among other components, contained corticosteroid drugs.

Results

The analysis of survival probabilities in relation to the indicated genotypes showed only an association between homozygosity for allele G of the NR3C1 BclI RFLP polymorphism and overall survival (univariate and multivariate hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.0, 7.6 and 5.2, 95% CI 1.4, 18.9, respectively). The association reflects a correlation with disease progression and prognosis, and may vary depending on risk of relapse.

Conclusion

A reduction in survival probability in children with ALL was associated with homozygosity for G allele of the NR3C1 BclI RFLP polymorphism, particularly in certain patient subgroups. Further analysis is required to replicate this finding and to understand the mechanism underlying the observed association.

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Acknowledgements

We are indebted to all the patients and their parents who consented to participate in this study. We are grateful to our colleagues Damian Labuda for discussion and biological material, Mark Bernstein for facilitating access to clinical data, and Alan Lovell for critical reading of the manuscript.

Isabelle Fleury has a studentship, and Maja Krajinovic and Daniel Sinnett scholarships from the Fonds de la recherche en santé du Québec. The Cancer Research Society, Inc. and Centre de Recherche, Hôpital Ste-Justine supported this study.

The authors have no conflicts of interest directly relevant to the content of this study.

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Authors and Affiliations

  1. Research Center, Sainte-Justine Hospital, Centre Hospitalier Universitaire Mère-Enfant, Montreal, Quebec, Canada

    Isabelle Fleury, Melanie Primeau, Agnes Doreau, Irina Costea, Albert Moghrabi, Daniel Sinnett &  Maja Krajinovic

  2. Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada

    Albert Moghrabi, Daniel Sinnett &  Maja Krajinovic

Authors
  1. Isabelle Fleury
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  2. Melanie Primeau
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  3. Agnes Doreau
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  4. Irina Costea
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  5. Albert Moghrabi
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  6. Daniel Sinnett
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  7. Maja Krajinovic
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Correspondence to Maja Krajinovic.

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Fleury, I., Primeau, M., Doreau, A. et al. Polymorphisms in Genes Involved in the Corticosteroid Response and the Outcome of Childhood Acute Lymphoblastic Leukemia. Am J Pharmacogenomics 4, 331–341 (2004). https://doi.org/10.2165/00129785-200404050-00006

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