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Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies

Blanco, Javier Ga; Edick, Mathew Ja; Hancock, Michael Lb; Winick, Naomi Jg; Dervieux, Thierrya; Amylon, Michael Dh; Bash, Robert Oi; Behm, Frederick Gc; Camitta, Bruce Mj; Pui, Ching-Hond,f; Raimondi, Susana Cc; Relling, Mary Va,e,f

Original Articles
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Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-ML) are serious complications that affect some patients after acute lymphoblastic leukemia (ALL) treatment. Genetic polymorphisms in the promoter of CYP3A4 (CYP3A4*1B) and in NAD(P)H:quinone oxidoreductase (NQO1609CT substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A5*3) affects CYP3A activity and the wild-type allele (CYP3A5*1) is in partial linkage with the CYP3A4*1B allele. We compared the genotype frequencies for the CYP3A5*3, the CYP3A4*1B and the NQO1609CT substitution in 224 children with ALL who did not develop t-ML (controls) and in 53 children with ALL who did develop the complication. The allele frequencies differed significantly among whites, blacks and Hispanics (P< 0.001 for CYP3A5*3, P< 0.001 for CYP3A4*1B and P = 0.004 for NQO1609), thus we performed the comparisons between ALL controls and t-ML patients after accounting for race. We found no differences in the CYP3A4*1B allele distribution between ALL controls and t-ML patients in whites (P = 0.339, 6.6% vs. 9.8%), blacks (P = 0.498, 93.8% vs. 87.5%) or Hispanics (P = 0.523, 39.1% vs. 25.0%). The frequencies for the NQO1609CT allele did not differ between control and t-ML groups in whites (P = 0.191, 35.0% vs. 44.9%), blacks (P= 0.664, 37.5% vs. 37.5%) or Hispanics (P = 0.447, 65.2% vs. 50.0%). We found no differences between the control and t-ML group in the incidence of homozygous CYP3A5*3 genotypes: 82.0% vs. 85.4% in whites (P = 0.403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P= 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL.

Departments of aPharmaceutical Sciences, bBiostatistics, cPathology, and dHematology-Oncology, St Jude Children's Research Hospital, Memphis TN, USA, Colleges of ePharmacy and fMedicine, University of Tennessee, Memphis, TN, USA, gUniversity of Texas Southwestern Medical Center, Dallas, TX, USA, hStanford University Medical Center Department of Pediatrics, Stanford, CA, USA, iChildren's Medical Center, Dallas, TX, USA and jMedical College of Wisconsin and the Midwest Children's Cancer Center, Milwaukee, WI, USA

Address correspondence to Dr Mary V. Relling, Department of Pharmaceutical Sciences. St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA Tel:+1 901 495 2348; fax: + 1 901 525 6869; e-mail: mary.relling@stjude.org

Received 3 June 2002 Accepted 29 July 2002

© 2002 Lippincott Williams & Wilkins, Inc.