title: Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma.
abstract: Neuroblastoma (NB) is a rare pediatric disease in Lebanon for which poor prognosis remains a major challenge. Genetic polymorphism of genes coding for drug‑metabolizing enzymes may influence the response of a patient to chemotherapy. This study investigates a possible association between CYP3A4/5 polymorphism and expression levels and survival in NB patients. All patients with stage III and IV NB diagnosed between 1993 and 2012 in three major hospitals in Beirut were included (n=27). Demographic information and survival time were obtained from medical records. CYP3A4 and CYP3A5 genotypes and expression levels were determined in archival tumors by polymerase chain reaction (PCR) and restriction fragment length polymorphism and quantitative PCR, respectively. Additionally, MYCN amplification was assessed. A Cox proportional hazards model was used to evaluate potential associations, adjusting for MYCN amplification. A statistically significant increase in the risk of mortality was observed in patients with MYCN amplification [hazard ratio (HR) 4.11, 95% confidence interval (CI) 1.14‑14.80]. Patients with CYP3A5 expression levels above the median had a lower risk of mortality (HR 0.61, 95% CI 0.21‑1.74) and patients with CYP3A4 expression levels above the median had a higher risk of mortality (HR 2.00, 95% CI 0.67‑5.90). CYP3A5*3/*3 homozygote mutants had a 4.3‑fold increase in the risk of mortality compared with that of homozygote wild‑type or heterozygote mutants (HR 4.30, 95% CI 0.56‑33.30). Carriers of the CYP3A4*1B mutant allele had a 52% lower risk of mortality compared with that of non‑carriers (HR 0.48, 95% CI 0.06‑3.76). Although the results of the present study did not achieve statistical significance, associations were observed, which indicates that CYP3A4 and CYP3A5 may modulate the clinical outcome of NB. Further studies with larger sample sizes are required to characterize the effects of the polymorphism and expression levels of CYP3A4/5 on the survival of patients with NB.
authors.affiliation: Department of Medical Lab Sciences, Faculty of Health Sciences, University of Balamand, Beirut 1100‑2807, Lebanon.
authors.forename: Mohamad H
authors.initials: MH
authors.lastname: Darwish
authors.affiliation: Department of Pediatric Oncology, Saint George Hospital University Medical Center, Beirut 1100‑2807, Lebanon.
authors.forename: Roula A
authors.initials: RA
authors.lastname: Farah
authors.affiliation: Department of Medical Lab Sciences, Faculty of Health Sciences, University of Balamand, Beirut 1100‑2807, Lebanon.
authors.forename: Ghada N
authors.initials: GN
authors.lastname: Farhat
authors.affiliation: Department of Pediatrics, Hotel Dieu De France Hospital, Beirut 1100‑2190, Lebanon.
authors.forename: Paul-Henri N
authors.initials: PH
authors.lastname: Torbey
authors.affiliation: Department of Pathology, Saint George Hospital University Medical Center, Beirut 1100‑2807, Lebanon.
authors.forename: Fatima A
authors.initials: FA
authors.lastname: Ghandour
authors.affiliation: Department of Pathology, University Medical Center ‑ Rizk Hospital, Beirut 11-3288, Lebanon.
authors.forename: Noha A
authors.initials: NA
authors.lastname: Bejjani-Doueihy
authors.affiliation: Department of Medical Lab Sciences, Faculty of Health Sciences, University of Balamand, Beirut 1100‑2807, Lebanon.
authors.forename: Hassan R
authors.initials: HR
authors.lastname: Dhaini
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003710:Demography; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein; D009367:Neoplasm Staging; D009423:Nervous System Neoplasms / Q000401:mortality / Q000473:pathology*; D009447:Neuroblastoma / Q000453:epidemiology / Q000401:mortality / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D015995:Prevalence; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human