Tantawy Azza A G, El-Bostany Eman A, Adly Amira A M, Abou El Asrar Mohammed, El-Ghouroury Eman A, Abdulghaffar Esmat E
Pediatric Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Blood Coagul Fibrinolysis. 2010 Jan;21(1):28-34. doi: 10.1097/MBC.0b013e32833135e9.
Genetic variations of the enzymes involved in chemotherapy metabolism in cancer patients may play a role in determining relapse and toxicity risks. Methotrexate is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5,10 methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is central to folate metabolism and has two common functional polymorphisms (C677>T and A1298>C). The present study aimed to assess the prevalence of MTHFR polymorphisms C677>T and A1298>C in Egyptian children with ALL and the relation to the frequency of drug-induced complications and relapse rate. Forty ALL patients were included in the study. They were treated according to modified ALL-BFM 90 protocol, and were followed up for 3.1-6.5 years. The severity and duration of hepatic, mucosal and infectious complications during therapy were reported. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay. The MTHFR C677>T polymorphic allele frequencies were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively among the studied ALL patients. The MTHFR A1298>C polymorphic allele frequencies were 40, 35, and 25% for AA, AC, and CC genotypes, respectively. Methotrexate therapy was significantly associated with increased grade III/IV toxicity in TT genotype: diarrhea in 81.3%, oral mucositis in 81.3%, elevated transaminases in 87.5%, neutropenia in 78.7% compared to values of 7.7, 7.7, 15.3, and 7.7% in CC genotype, respectively (P < 0.0001, P < 0.0001, P < 0.0001, and P = 0.03). The 677 TT genotype was significantly associated with relapse in 5 years in 56.3%, compared to 18.2% in CT and 0% in CC alleles. The overall 5 years survival was significantly lower in 677 TT (50%) compared with CC genotypes (92.3%) (P = 0.001). No significant relation was found between MTHFR A1298C polymorphism and the risks of therapy induced complications or relapse rate in the studied ALL patients. MTHFR TT genotype is significantly associated with increased mucosal and hepatic toxicity during methotrexate therapy as well as increased relapse rate in childhood ALL. Because of the relatively high prevalence of the TT genotype in the studied Egyptian children with ALL, MTHFR gene polymorphisms should be studied in large multicenter studies; and dosage modification of methotrexate in the ALL treatment protocols should be considered based on the MTHFR gene pattern.
癌症患者中参与化疗代谢的酶的基因变异可能在决定复发风险和毒性风险方面发挥作用。甲氨蝶呤是急性淋巴细胞白血病（ALL）治疗中的关键药物；它通过亚甲基四氢叶酸还原酶（MTHFR）阻断5,10 - 亚甲基四氢叶酸向5 - 亚甲基四氢叶酸的转化来抑制DNA复制。MTHFR是叶酸代谢的核心，有两种常见的功能多态性（C677>T和A1298>C）。本研究旨在评估埃及ALL儿童中MTHFR多态性C677>T和A1298>C的患病率以及与药物诱导并发症频率和复发率的关系。40例ALL患者纳入研究。他们按照改良的ALL - BFM 90方案进行治疗，并随访3.1 - 6.5年。报告了治疗期间肝脏、黏膜和感染性并发症的严重程度和持续时间。采用基于聚合酶链反应的限制性片段长度多态性分析进行MTHFR基因分型。在研究的ALL患者中，MTHFR C677>T多态性等位基因频率在TT、CT和CC基因型中分别为40%、27.5%和32.5%。MTHFR A1298>C多态性等位基因频率在AA、AC和CC基因型中分别为40%、35%和25%。甲氨蝶呤治疗与TT基因型中III/IV级毒性增加显著相关：腹泻发生率为81.3%，口腔黏膜炎发生率为81.3%，转氨酶升高发生率为87.5%，中性粒细胞减少发生率为78.7%，而CC基因型中分别为7.7%、7.7%、15.3%和7.7%（P < 0.0001，P < 0.0001，P < 0.0001，P = 0.03）。677 TT基因型与5年内复发显著相关，复发率为56.3%，而CT基因型为18.2%，CC等位基因为0%。677 TT基因型的总体5年生存率（50%）显著低于CC基因型（92.3%）（P = 0.001）。在研究的ALL患者中，未发现MTHFR A1298C多态性与治疗诱导并发症风险或复发率之间存在显著关系。MTHFR TT基因型与甲氨蝶呤治疗期间黏膜和肝脏毒性增加以及儿童ALL复发率增加显著相关。由于在研究的埃及ALL儿童中TT基因型患病率相对较高，应在大型多中心研究中研究MTHFR基因多态性；并且应根据MTHFR基因模式考虑在ALL治疗方案中调整甲氨蝶呤剂量。
