Polymorphisms in Genes Involved in the Corticosteroid Response and the Outcome of Childhood Acute Lymphoblastic Leukemia
- 59 Downloads
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.
The aim of the study was to analyze the role of these polymorphisms in the outcome of a disease treated with CS drugs.
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.
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.
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.
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.
- 11.Chabner BA, Allegra CA, Curt GA, et al. Antineoplastic agents. In: Hardman JG, Gilman AG, Limbird LE, editors. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1996Google Scholar
- 13.Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs. In: Hardman JG, Limbird LE, Gilman AG, editors. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1996: 1649–78Google Scholar
- 49.Huizenga NA, Koper JW, de Lange P, et al. Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab 1998; 83: 47–54PubMedCrossRefGoogle Scholar
- 56.Dobson MG, Redfern CP, Unwin N, et al. The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. J Clin Endocrinol Metab 2001; 86: 2270–4PubMedCrossRefGoogle Scholar