TY - JOUR

T1 - The impact of CYP3A5*3 on risk and prognosis in childhood acute lymphoblastic leukemia

AU - Borst, Louise

AU - Wallerek, Sandra

AU - Dalhoff, Kim

AU - Rasmussen, Kirsten

AU - Wesenberg, Finn

AU - Wehner, Peder Skov

AU - Schmiegelow, Kjeld

N1 - © 2011 John Wiley & Sons A/S.

PY - 2011

Y1 - 2011

N2 - Objectives: Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood; however, little is known of the molecular etiology and environmental exposures causing the disease. Cytochrome P450 3A5 (CYP3A5) plays a crucial role in the catalytic oxidation of endogenous metabolites and toxic substances, including chemotherapeutic agents. The aim of this study was to investigate the role of a single-nucleotide polymorphism (CYP3A5*3 6986A>G), which renders low enzyme activity, in the risk of developing ALL and in the outcome for children with ALL. Patients and methods: Six hundred and sixteen childhood patients with ALL and 203 controls were genotyped by allelic discrimination. Results: Individuals with the A allele had a 64% increased risk of developing childhood ALL (odds ratio = 1.64; 95% CI, 1.009-2.657). In general, event-free survival (EFS) did not differ in relation to CYP3A5 genotype. However, for patients with T-ALL, presence of the A allele was associated with better prognosis (EFS = 94.1%), while patients with the low-activity GG genotype only had an EFS of 61.5% (P = 0.015). Thus, for patients with T-ALL having no A allele and therefore low expression of CYP3A5, the risk of experiencing an event was almost eight times higher compared to those having at least one A allele (P = 0.045, hazard ratio = 7.749; 95% CI, 1.044-57.52). Conclusions: This study shows that genetics may play a role in the risk of developing childhood ALL and indicates that improved treatment stratification of childhood patients with ALL may require addition of host genetic information.

AB - Objectives: Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood; however, little is known of the molecular etiology and environmental exposures causing the disease. Cytochrome P450 3A5 (CYP3A5) plays a crucial role in the catalytic oxidation of endogenous metabolites and toxic substances, including chemotherapeutic agents. The aim of this study was to investigate the role of a single-nucleotide polymorphism (CYP3A5*3 6986A>G), which renders low enzyme activity, in the risk of developing ALL and in the outcome for children with ALL. Patients and methods: Six hundred and sixteen childhood patients with ALL and 203 controls were genotyped by allelic discrimination. Results: Individuals with the A allele had a 64% increased risk of developing childhood ALL (odds ratio = 1.64; 95% CI, 1.009-2.657). In general, event-free survival (EFS) did not differ in relation to CYP3A5 genotype. However, for patients with T-ALL, presence of the A allele was associated with better prognosis (EFS = 94.1%), while patients with the low-activity GG genotype only had an EFS of 61.5% (P = 0.015). Thus, for patients with T-ALL having no A allele and therefore low expression of CYP3A5, the risk of experiencing an event was almost eight times higher compared to those having at least one A allele (P = 0.045, hazard ratio = 7.749; 95% CI, 1.044-57.52). Conclusions: This study shows that genetics may play a role in the risk of developing childhood ALL and indicates that improved treatment stratification of childhood patients with ALL may require addition of host genetic information.

U2 - http://dx.doi.org/10.1111/j.1600-0609.2011.01608.x

DO - http://dx.doi.org/10.1111/j.1600-0609.2011.01608.x

M3 - Journal article

VL - 86

SP - 477

EP - 483

JO - European Journal of Haematology

JF - European Journal of Haematology

SN - 0902-4441

IS - 6

ER -