Timuragaoglu A, Dizlek S, Uysalgil N, Tosun O, Yamac K
Department of Hematology, School of Medicine, Akdeniz University, Antalya, Turkey.
Ann Hematol. 2006 Dec;85(12):863-8. doi: 10.1007/s00277-006-0175-4. Epub 2006 Aug 31.
Methylenetetrahydrofolate reductase (MTHFR) is one of the most critical enzyme in folic acid metabolism, and it converts 5,10-MTHF to 5-MTHF. 5,10-MTHF is required for conversion of uridilate to thymidylate. On the other side, MTHFR enzyme causes methylation of homocysteine into methionine, leading to methylation of DNA. Chemotherapeutic agents have different effects, but DNA is the target for most of them. Because folate is the cornerstone in DNA synthesis, we analysed herein if the polymorphisms in MTHFR gene can alter the susceptibility of lymphoproliferative disease risk and if it has an effect on chemotherapy response. One hundred fifty-six patients with lymphoid malignancies and 82 healthy controls were included into the study. Neither gene frequencies nor allel frequencies were found to increase lymphoproliferative disease risk significantly in both overall group and subgroups. Although it was not statistically significant, we found a 2.7-fold increased risk in acute lymphocytic leukaemia (ALL)/Burkitt lymphoma patients with TT genotype [odds ratio (OR), 2.7; 95% confidence interval (CI), 0.88-8.2] than CC genotype but a 1.7-fold decreased risk with TT genotype in diffuse large B-cell lymphoma (DLBCL; OR, 0.58; 95% CI, 0.17-1.88) and a 1.8-fold decreased risk in Hodgkin's lymphoma with TT genotype (OR, 0.55; 95% CI, 0.10-2.87) than CC genotype. The chemotherapy response was analysed in DLBCL, Hodgkin's lymphoma and ALL/Burkitt's lymphoma because these patients received standard chemotherapy protocols. No significant difference was detected between responder and non-responders according to MTHFR T677C polymorphism, but the patients who had TT genotype respond 1.75-fold worse than CC (OR, 0.57; 95% CI, 0.07-4.64) in ALL patients (p=0.59), and in DLBCL, CT genotype revealed a 1.8-fold worse response than CC genotype (OR, 0.54; 95% CI, 0.17-1.7), but TT genotype revealed 2.6-fold better response rates than patients with CC genotype (OR, 2.6; 95% CI, 0.26-26.8). As a conclusion, MTHFR C677T polymorphism does not increase the risk of lymphoproliferative disease, and it does not have an effect on chemotherapy response significantly; however, the patients with TT genotype have a slightly increased risk for ALL, and they also respond worse than CC genotype. TT genotype slightly decreases the risk of DLBCL, and the patients have much favorable response rates.
亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢中最关键的酶之一，它将5,10 - 亚甲基四氢叶酸（5,10 - MTHF）转化为5 - 甲基四氢叶酸（5 - MTHF）。尿嘧啶核苷酸转化为胸苷酸需要5,10 - MTHF。另一方面，MTHFR酶促使同型半胱氨酸甲基化生成甲硫氨酸，进而导致DNA甲基化。化疗药物有不同的作用，但大多数药物的作用靶点是DNA。由于叶酸是DNA合成的基石，我们在此分析MTHFR基因多态性是否会改变淋巴增殖性疾病的易感性，以及它是否对化疗反应有影响。本研究纳入了156例淋巴系统恶性肿瘤患者和82例健康对照。在总体组和亚组中，均未发现基因频率和等位基因频率会显著增加淋巴增殖性疾病的风险。虽然无统计学意义，但我们发现急性淋巴细胞白血病（ALL）/伯基特淋巴瘤患者中，TT基因型的风险比CC基因型增加了2.7倍[比值比（OR），2.7；95%置信区间（CI），0.88 - 8.2]，而在弥漫性大B细胞淋巴瘤（DLBCL）中，TT基因型的风险比CC基因型降低了至1.7倍（OR，0.58；95% CI，0.17 - 1.88），在霍奇金淋巴瘤中，TT基因型的风险比CC基因型降低了1.8倍（OR，0.55；95% CI，0.10 - 2.87）。对DLBCL、霍奇金淋巴瘤和ALL/伯基特淋巴瘤患者的化疗反应进行了分析，因为这些患者接受了标准化疗方案。根据MTHFR T677C多态性，在反应者和无反应者之间未检测到显著差异，但在ALL患者中，TT基因型患者的反应比CC基因型差1.75倍（OR，0.57；95% CI，0.07 - 4.64）（p = 0.59），在DLBCL中，CT基因型的反应比CC基因型差1.8倍（OR，0.54；95% CI，0.17 - 1.7），但TT基因型患者的反应率比CC基因型患者高2.6倍（OR，2.6；95% CI，0.26 - 26.8）。总之，MTHFR C677T多态性不会增加淋巴增殖性疾病的风险，也不会对化疗反应产生显著影响；然而，TT基因型患者患ALL的风险略有增加，且反应比CC基因型患者差。TT基因型会略微降低DLBCL的风险，且患者的反应率更优。
