Polymorphisms in genes involved in the corticosteroid response and the outcome of childhood acute lymphoblastic leukemia.
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.


OBJECTIVE
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.


CONCLUSIONS
A reduction in survival probability in children with ALL was associated with homozygosity for G allele of the NR3C1BclI RFLP polymorphism, particularly in certain patient subgroups. Further analysis is required to replicate this finding and to understand the mechanism underlying the observed association.
Fleury
Isabelle
I
Research Center, Sainte-Justine Hospital, Centre Hospitalier Universitaire Mère-Enfant, Montreal, Quebec, Canada.
Primeau
Melanie
M
Doreau
Agnes
A
Costea
Irina
I
Moghrabi
Albert
A
Sinnett
Daniel
D
Krajinovic
Maja
M
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D011336:Probability; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015996:Survival Rate
D000305:Adrenal Cortex Hormones; D011965:Receptors, Glucocorticoid; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human