Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma

Darwish,Mohamad  H.; Farah,Roula  A.; Farhat,Ghada  N.; Torbey,Paul‑Henri  N.; Ghandour,Fatima  A.; Bejjani‑Doueihy,Noha  A.; Dhaini,Hassan  R.

doi:10.3892/mmr.2014.2835

Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma

Authors:
- Mohamad H. Darwish
- Roula A. Farah
- Ghada N. Farhat
- Paul‑Henri N. Torbey
- Fatima A. Ghandour
- Noha A. Bejjani‑Doueihy
- Hassan R. Dhaini
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Affiliations: Department of Medical Lab Sciences, Faculty of Health Sciences, University of Balamand, Beirut 1100‑2807, Lebanon, Department of Pediatric Oncology, Saint George Hospital University Medical Center, Beirut 1100‑2807, Lebanon, Department of Pediatrics, Hotel Dieu De France Hospital, Beirut 1100‑2190, Lebanon, Department of Pathology, Saint George Hospital University Medical Center, Beirut 1100‑2807, Lebanon, Department of Pathology, University Medical Center ‑ Rizk Hospital, Beirut 11-3288, Lebanon
Published online on: October 31, 2014 https://doi.org/10.3892/mmr.2014.2835
Pages: 1462-1468

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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.

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1	Maris JM: Recent advances in neuroblastoma. N Engl J Med. 362:2202–2211. 2010. View Article : Google Scholar : PubMed/NCBI
2	Howlader N, Noone A, Krapcho M, et al: SEER Cancer Statistics Review, 1975–2011. National Cancer Institute; Bethesda, MD: 2012, http://seer.cancer.gov/csr/1975_2011/. Accessed August 14, 2014
3	London WB, Castleberry RP, Matthay KK, et al: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol. 23:6459–6465. 2005. View Article : Google Scholar : PubMed/NCBI
4	Lebanese Ministry of Public Health and Epidemiology Surveillance Program. National cancer registry. 2007, http://www.moph.gov.lb/Prevention/Surveillance/Pages/Cancer.aspx.2010. Accessed December 9, 2013
5	Ries L, Smith M, Gurney J, Linet M, Tamra T, Young J and Bunin G: Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. NIH publication no. 99-4649. National Cancer Institute; Bethesda, MD: 1999
6	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007. View Article : Google Scholar : PubMed/NCBI
7	Brodeur GM: Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3:203–216. 2003. View Article : Google Scholar : PubMed/NCBI
8	Kushner BH, Gilbert F and Helson L: Familial neuroblastoma. Case reports, literature review, and etiologic considerations. Cancer. 57:1887–1893. 1986. View Article : Google Scholar : PubMed/NCBI
9	Brodeur GM, Seeger RC, Schwab M, Varmus HE and Bishop JM: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 224:1121–1124. 1984. View Article : Google Scholar : PubMed/NCBI
10	Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY and Hammond D: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 313:1111–1116. 1985. View Article : Google Scholar : PubMed/NCBI
11	Tonini GP and Romani M: Genetic and epigenetic alterations in neuroblastoma. Cancer Lett. 197:69–73. 2003. View Article : Google Scholar : PubMed/NCBI
12	Kushner BH, LaQuaglia MP, Bonilla MA, et al: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol. 12:2607–2613. 1994.PubMed/NCBI
13	Simon T, Längler A, Berthold F, Klingebiel T and Hero B: Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma: results of a phase 2 trial. J Pediatr Hematol Oncol. 29:101–106. 2007. View Article : Google Scholar : PubMed/NCBI
14	Daly AK: Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam Clin Pharmacol. 17:27–41. 2003. View Article : Google Scholar : PubMed/NCBI
15	Ashton LJ, Murray JE, Haber M, Marshall GM, Ashley DM and Norris MD: Polymorphisms in genes encoding drug metabolizing enzymes and their influence on the outcome of children with neuroblastoma. Pharmacogenet Genomics. 17:709–717. 2007. View Article : Google Scholar : PubMed/NCBI
16	Huang Z, Roy P and Waxman DJ: Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol. 59:961–972. 2000. View Article : Google Scholar : PubMed/NCBI
17	Petros WP, Hopkins PJ, Spruill S, et al: Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol. 23:6117–6125. 2005. View Article : Google Scholar : PubMed/NCBI
18	Walker D, Flinois JP, Monkman SC, et al: Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide. Biochem Pharmacol. 47:1157–1163. 1994. View Article : Google Scholar : PubMed/NCBI
19	Dennison JB, Jones DR, Renbarger JL and Hall SD: Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther. 321:553–563. 2007. View Article : Google Scholar : PubMed/NCBI
20	Relling MV, McLeod HL, Bowman LC and Santana VM: Etoposide pharmacokinetics and pharmacodynamics after acute and chronic exposure to cisplatin. Clin Pharmacol Ther. 56:503–511. 1994. View Article : Google Scholar : PubMed/NCBI
21	McCune JS, Risler LJ, Phillips BR, Thummel KE, Blough D and Shen DD: Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos. 33:1074–1081. 2005. View Article : Google Scholar : PubMed/NCBI
22	Bosch TM, Meijerman I, Beijnen JH and Schellens JH: Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin Pharmacokinet. 45:253–285. 2006. View Article : Google Scholar : PubMed/NCBI
23	van Schaik RH, de Wildt SN, van Iperen NM, Uitterlinden AG, van den Anker JN and Lindemans J: CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians. Clin Chem. 46:1834–1836. 2000.PubMed/NCBI
24	van Schaik RH, van der Heiden IP, van den Anker JN and Lindemans J: CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem. 48:1668–1671. 2002.PubMed/NCBI
25	Raggi CC, Bagnoni ML, Tonini GP, et al: Real-time quantitative PCR for the measurement of MYCN amplification in human neuroblastoma with the TaqMan detection system. Clin Chem. 45:1918–1924. 1999.PubMed/NCBI
26	Peirson SN, Butler JN and Foster RG: Experimental validation of novel and conventional approaches to quantitative real-time PCR data analysis. Nucleic Acids Res. 31:e732003. View Article : Google Scholar : PubMed/NCBI
27	Lamba JK, Lin YS, Schuetz EG and Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 54:1271–1294. 2002. View Article : Google Scholar : PubMed/NCBI
28	Busi F and Cresteil T: Phenotyping-genotyping of alternatively spliced genes in one step: study of CYP3A5^*3 polymorphism. Pharmacogenet Genomics. 15:433–439. 2005. View Article : Google Scholar : PubMed/NCBI
29	Sinues B, Vicente J, Fanlo A, et al: CYP3A5^3 and CYP3A4^1B allele distribution and genotype combinations: differences between Spaniards and Central Americans. Ther Drug Monit. 29:412–416. 2007. View Article : Google Scholar : PubMed/NCBI
30	Amirimani B, Ning B, Deitz AC, Weber BL, Kadlubar FF and Rebbeck TR: Increased transcriptional activity of the CYP3A4^*1B promoter variant. Environ Mol Mutagen. 42:299–305. 2003. View Article : Google Scholar
31	Lim HJ, Gill S, Speers C, et al: Impact of irinotecan and oxaliplatin on overall survival in patients with metastatic colorectal cancer: a population-based study. J Oncol Pract. 5:153–158. 2009. View Article : Google Scholar : PubMed/NCBI
32	Gellner K, Eiselt R, Hustert E, et al: Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics. 11:111–121. 2001. View Article : Google Scholar : PubMed/NCBI
33	Dhaini HR, Thomas DG, Giordano TJ, et al: Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma. J Clin Oncol. 21:2481–2485. 2003. View Article : Google Scholar : PubMed/NCBI
34	Borst L, Wallerek S, Dalhoff K, Rasmussen KK, Wesenberg F, Wehner PS and Schmiegelow K: The impact of CYP3A5^*3 on risk and prognosis in childhood acute lymphoblastic leukemia. Eur J Haematol. 86:477–483. 2011. View Article : Google Scholar : PubMed/NCBI
35	Gréen H, Khan MS, Jakobsen-Falk I, Avall-Lundqvist E and Peterson C: Impact of CYP3A5^*3 and CYP2C8-HapC on paclitaxel/carboplatin-induced myelosuppression in patients with ovarian cancer. J Pharm Sci. Jun 23–2011.(Epub ahead of print).
36	Maquat LE: When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA. 1:453–465. 1995.PubMed/NCBI
37	Kuehl P, Zhang J, Lin Y, et al: Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 27:383–391. 2001. View Article : Google Scholar : PubMed/NCBI
38	Lewis AD, Lau DH, Durán GE, Wolf CR and Sikic BI: Role of cytochrome P-450 from the human CYP3A gene family in the potentiation of morpholino doxorubicin by human liver microsomes. Cancer Res. 52:4379–4384. 1992.PubMed/NCBI
39	Xie HG, Wood AJ, Kim RB, Stein CM and Wilkinson GR: Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 5:243–272. 2004. View Article : Google Scholar : PubMed/NCBI
40	Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ and Wilkinson GR: CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4^*1B5′-promoter region polymorphism. Clin Pharmacol Ther. 68:82–91. 2000. View Article : Google Scholar : PubMed/NCBI
41	Westlind A, Löfberg L, Tindberg N, Andersson TB and Ingelman-Sundberg M: Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region. Biochem Biophys Res Commun. 259:201–205. 1999. View Article : Google Scholar : PubMed/NCBI
42	Fisher CD, Lickteig AJ, Augustine LM, Ranger-Moore J, Jackson JP, Ferguson SS and Cherrington NJ: Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. Drug Metab Dispos. 37:2087–2094. 2009. View Article : Google Scholar : PubMed/NCBI
43	Rodríguez-Antona C, Donato MT, Pareja E, Gómez-Lechón MJ and Castell JV: Cytochrome P-450 mRNA expression in human liver and its relationship with enzyme activity. Arch Biochem Biophys. 393:308–315. 2001. View Article : Google Scholar : PubMed/NCBI
44	Garcia-Martín E, Martínez C, Pizarro RM, Garcia-Gamito FJ, Gullsten H, Raunio H and Agúndez JA: CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin Pharmacol Ther. 71:196–204. 2002. View Article : Google Scholar : PubMed/NCBI
45	Ball SE, Scatina J, Kao J, et al: Population distribution and effects on drug metabolism of a genetic variant in the 5′ promoter region of CYP3A4. Clin Pharmacol Ther. 66:288–294. 1999. View Article : Google Scholar : PubMed/NCBI
46	Miyoshi Y, Ando A, Takamura Y, Taguchi T, Tamaki Y and Noguchi S: Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues. Int J Cancer. 97:129–132. 2002. View Article : Google Scholar : PubMed/NCBI