Blanco Javier G, Edick Mathew J, Hancock Michael L, Winick Naomi J, Dervieux Thierry, Amylon Michael D, Bash Robert O, Behm Frederick G, Camitta Bruce M, Pui Ching-Hon, Raimondi Susana C, Relling Mary V
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis TN 38105, USA.
Pharmacogenetics. 2002 Nov;12(8):605-11. doi: 10.1097/00008571-200211000-00004.
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 (CYP3A41B) and in NAD(P)H:quinone oxidoreductase (NQO1609C-->T substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A53) affects CYP3A activity and the wild-type allele (CYP3A51) is in partial linkage with the CYP3A41B allele. We compared the genotype frequencies for the CYP3A53, the CYP3A41B and the NQO1609C-->T 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 CYP3A53, 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 NQO1609C-->T 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 CYP3A53 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.
治疗相关的急性髓系白血病和骨髓增生异常综合征（t-ML）是急性淋巴细胞白血病（ALL）治疗后影响部分患者的严重并发症。细胞色素P450 3A4（CYP3A41B）启动子及烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶（NQO1 609C→T替换）中的基因多态性与t-ML风险相关。细胞色素P450 3A5（CYP3A53）中的一种多态性影响CYP3A活性，野生型等位基因（CYP3A51）与CYP3A41B等位基因部分连锁。我们比较了224例未发生t-ML的ALL儿童（对照组）和53例发生该并发症的ALL儿童中CYP3A53、CYP3A41B及NQO1 609C→T替换的基因型频率。白种人、黑种人和西班牙裔之间的等位基因频率存在显著差异（CYP3A53为P < 0.001，CYP3A41B为P < 0.001，NQO1 609为P = 0.004），因此我们在考虑种族因素后对ALL对照组和t-ML患者进行了比较。我们发现，白种人（P = 0.339，6.6%对9.8%）、黑种人（P = 0.498，93.8%对87.5%）或西班牙裔（P = 0.523，39.1%对25.0%）的ALL对照组和t-ML患者之间，CYP3A41B等位基因分布无差异。白种人（P = 0.191，35.0%对44.9%）、黑种人（P = 0.664，37.5%对37.5%）或西班牙裔（P = 0.447，65.2%对50.0%）的对照组和t-ML组之间，NQO1 609C→T等位基因频率无差异。我们发现对照组和t-ML组纯合CYP3A53基因型的发生率无差异：白种人为82.0%对85.4%（P = 0.403），黑种人为6.5%对12.5%（P = 0.508），西班牙裔为69.6%对75.0%（P = 0.663）。我们的数据不支持常见的CYP3A4、NQO1或CYP3A5多态性与接受ALL治疗儿童的t-ML风险之间存在关联。
