Wiemels J L, Smith R N, Taylor G M, Eden O B, Alexander F E, Greaves M F
Leukaemia Research Fund Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4004-9. doi: 10.1073/pnas.061408298. Epub 2001 Mar 13.
Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.
低叶酸摄入量以及由于亚甲基四氢叶酸还原酶（MTHFR）基因多态性导致的叶酸代谢改变，与神经管缺陷、血管疾病和某些癌症的发病率增加有关。MTHFR的多态性变体导致胸苷池增加和DNA合成质量提高，这可能为白血病，特别是那些有易位的白血病的发生提供一些保护。我们现在报告MTHFR基因多态性在儿童白血病三个亚组中的关联：伴有MLL重排的婴儿淋巴细胞白血病或髓细胞白血病，以及伴有TEL-AML1融合或超二倍体核型的儿童淋巴细胞白血病。对253名儿童白血病患者和200名健康新生儿对照进行了MTHFR基因多态性677位核苷酸（C→T）和1298位核苷酸（A→C）的基因分型。与对照组相比，C677T携带者与伴有MLL易位的白血病（MLL+，n = 37）之间存在显著关联[校正比值比（OR）= 0.36，95%置信区间（CI）为0.15 - 0.85；P = 0.017]。A1298C等位基因未显示出这种保护作用（OR = 1.14）。相反，在超二倍体白血病（n = 138）中观察到A1298C纯合子（CC；OR = 0.26，95%CI为0.07 - 0.81）和C677T纯合子（TT；OR = 0.49，95%CI为0.20 - 1.17）的关联。对于TEL-AML1+白血病（n = 78），两种多态性均未显示出显著关联。等位基因关联的这些差异可能表明这两个等位基因在改变叶酸和一碳代谢物池以及影响DNA合成和甲基化途径后的能力方面具有不同特性，但在更大规模的后续研究之前应谨慎看待。这些数据提供了证据，表明分子定义的儿童白血病亚组具有不同的病因，也提示了叶酸在儿童白血病发生中的作用。
