1. INTRODUCTION
Non-Hodgkin lymphoma (NHL), the fourth most common malignancy across the pediatric age spectrum, is a heterogeneous group of lymphoid malignancies.1, 2 In children, NHL comprises of four main categories: Burkitt lymphoma (BL), lymphoblastic lymphoma (LBL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL).3, 4 The current overall survival (OS) rate of pediatric NHL is >80% due to dramatic progress in developing risk-adapted curative therapy.1
Folate is a vital coenzyme in DNA synthesis. Methylenetetrahydrofolate reductase (MTHFR) plays a key role in intracellular folate metabolism by converting 5,10-methylenetetrahydrofolate (5,10-MTHF), to 5-methyltetrahydrofolate (5-MTHF), which is the major circulating form of folate and is essential for protein synthesis and nucleic acid methylation.5-7 The two most extensively studied single-nucleotide polymorphisms (SNPs) of MTHFR concerning NHL risk and treatment outcome are the C677T variant (Ala222Val, rs1801133) and the A1298C variant (Glu 429Ala, rs1801131); both dampening enzyme activity by 40-70 %.5, 8, 9 Many studies have investigated the relationships between polymorphisms in the folate-metabolizing MTHFR gene and NHL. Several case–control studies have shown that the correlation between C677T/A1298C and NHL risk could be modified by ethnicity.10-15 Moreover, MTHFR gene variants play a significant role in the outcome of patients with NHL. Nevertheless, conclusions remain inconsistent. Analysis of polymorphisms in the folate pathway genes might help to reduce chemotherapy toxicity and improve survival by indicating when dose adjustments or alternative treatments are needed.7
Recently, there has been growing interest in the effects of the C677T and A1298C on the survival of patients with cancer. Most studies have focused on the survival of pediatric acute lymphoblastic leukemia (ALL),5, 16-18 osteosarcoma,19 adult NHL,7 and colorectal cancer (CRC),20-24 whereas the relationships between clinical outcome and folate pathway gene variants in pediatric NHL have been poorly investigated. Therefore, the main purpose of the present retrospective study was to evaluate the influence of the C677T and A1298C polymorphisms on the survival of pediatric NHL treated according to the modified NHL-BFM (Berlin-Frankfurt-Münster) 95 protocol.