%0 Journal Article
%T Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies
%A Hiroko Fukushima
%A Takashi Fukushima
%A Aiko Sakai
%A Ryoko Suzuki
%A Ryoko Nakajima-Yamaguchi
%A Chie Kobayashi
%A Atsushi Iwabuchi
%A Makoto Saito
%A Ai Yoshimi
%A Tomohei Nakao
%A Keisuke Kato
%A Masahiro Tsuchida
%A Hideto Takahashi
%A Kazutoshi Koike
%A Nobutaka Kiyokawa
%A Emiko Noguchi
%A Ryo Sumazaki
%J Leukemia Research and Treatment
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/238528
%X Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin¡¯s lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 ( ). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies. 1. Introduction Childhood cancer is a rare disease affecting 1 in 70,000 children aged 14 years and younger [1, 2]. Lymphoid malignancy, including leukemia and lymphoma, is the most common childhood cancer, accounting for 40% of all pediatric malignancies [2]. During the last 20 years, survival rates for pediatric acute lymphoblastic leukemia (ALL) and non-Hodgkin¡¯s lymphoma (NHL) have improved dramatically, mostly due to improvement of chemotherapy, allogeneic hematopoietic stem cell transplantation, and diagnostic techniques, with expected cure rates higher than 80% for pediatric lymphoid malignancy [1¨C3]. Methotrexate (MTX) is one of the key drugs for cancer treatment and a proven critical component for pediatric ALL and NHL [1, 4, 5]. MTX interrupts the folic acid cycle by inhibiting two enzymes (Figure 1). Firstly, as an analog of folate, MTX is a powerful competitive inhibitor of dihydrofolate reductase (DHFR) [6, 7]. DHFR is responsible for converting folates to their active form tetrahydrofolate, a substrate of thymidylate synthase (TS), to convert deoxyuridine monophosphate to deoxythymidine-5¡ä-monophosphate resulting in DNA synthesis. Secondly, the polyglutamated forms of MTX inhibit the activity of TS directly [6, 8]. High-dose MTX (HD-MTX) treatment has been proven for
%U http://www.hindawi.com/journals/lrt/2013/238528/