Influence of Methylenetetrahydrofolate Reductase C677T, A1298C, and G80A Polymorphisms on the Survival of Pediatric Patients with Acute Lymphoblastic Leukemia
The influence of genic polymorphisms involved in metabolism of chemotherapeutic agents as the methotrexate (MTX) has been studied mainly in acute lymphoblastic leukemia (ALL) of childhood. Advances in treatment may be attributed to identification of prognostic factors added to chemotherapy protocol. The aim of this study was to analyze the association of the C677T, A1298C, and G80A polymorphisms on MTHFR gene and on the overall survival of pediatric patients with lymphoblastic leukemia treated with MTX according to the Brazilian protocol in 187 months. The C677T and G80A polymorphisms were genotyped by PCR-RFLP and A1298C polymorphism by allele-specific PCR. We observed that ALL patients presented rate (dead/alive) of 0.36 for the 677CC genotype, corresponding also to lower overall survival ; on the other hand, the 677TT genotype showed a better survival (98%). Thus, we believe that patients with 80AA genotype presented a small reduction in MTX plasma level, suggesting that ALL children, carrying the 80AA genotype, showed a high toxicity to MTX . 1. Introduction Leukemia is the most common childhood cancer. Recently the influence of polymorphisms in different genes is involved on the metabolism of chemotherapeutic agents and it has been studied especially in childhood acute lymphoblastic leukemia (ALL) [1]. Despite actual chemotherapy protocols cure almost 80% of pediatric patients with ALL, the majority of adult patients still die from this disease. Advances in cure rates in children could be attributable to identification of prognostic features together with the intensified chemotherapy and improved supportive therapy [2]. Genetic polymorphisms in patients with ALL can alter drug-metabolizing enzymes, transporters, and targets; therefore, they can influence both efficacy and toxicity of chemotherapeutic agents. Actually this type of genetic polymorphisms is not used in a specific treatment; however, they could be responsible for an altered sensitivity of leukemic cells to drugs [3]. The pharmacological pathway of MTX is useful to identify genes and polymorphisms that influence the response to chemotherapy for ALL. An important enzyme in the folate/methotrexate metabolism pathway is 5,10-methylenetetrahydrofolate reductase (MTHFR), which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in the folic acid cycle [3]. The MTHFR plays an important role in the folate metabolism and differences in its activity due to these two genic variants might modify the modulation of therapeutic response to antifolate
References
[1]
M. H. Cheok and W. E. Evans, “Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy,” Nature Reviews Cancer, vol. 6, no. 2, pp. 117–129, 2006.
[2]
C. H. Pui and W. E. Evans, “Treatment of acute lymphoblastic leukemia,” The New England Journal of Medicine, vol. 354, no. 2, pp. 166–178, 2006.
[3]
L. B. Bailey and J. F. Gregory III, “Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement,” Journal of Nutrition, vol. 129, no. 5, pp. 919–922, 1999.
[4]
K. Robien and C. M. Ulrich, “5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview,” American Journal of Epidemiology, vol. 157, no. 7, pp. 571–582, 2003.
[5]
L. H. Matherly and I. D. Goldman, “Membrane transport of folates,” Vitamins and Hormones, vol. 66, pp. 403–456, 2003.
[6]
G. M. Shaw, E. J. Lammer, H. Zhu, M. W. Baker, E. Neri, and R. H. Finnell, “Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida,” American Journal of Medical Genetics, vol. 108, no. 1, pp. 1–6, 2002.
[7]
M. O. Cazé, D. Bueno, and M. E. Santos, “Referential study of a chemotherapy protocol for acute lymphocytic leukemia in childhood,” Revista HCPA, vol. 30, no. 1, pp. 5–12, 2010.
[8]
S. A. Miller, D. D. Dykes, and H. F. Polesky, “A simple salting out procedure for extracting DNA from human nucleated cells,” Nucleic Acids Research, vol. 16, no. 3, p. 1215, 1988.
[9]
P. Frosst, H. J. Blom, R. Milos et al., “A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase,” Nature Genetics, vol. 10, no. 1, pp. 111–113, 1995.
[10]
P. M. Biselli, A. R. Guerzoni, E. M. Goloni-Bertollo, M. F. de Godoy, J. A. B. Abou-Chahla, and é. C. Pavarino-Bertelli, “MTHFR genetic variability on coronary artery disease development,” Revista da Associacao Medica Brasileira, vol. 55, no. 3, pp. 274–278, 2009.
[11]
A. Chango, N. Emery-Fillon, G. P. De Courcy et al., “A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia,” Molecular Genetics and Metabolism, vol. 70, no. 4, pp. 310–315, 2000.
[12]
R. De Jonge, W. J. E. Tissing, J. H. Hooijberg et al., “Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia,” Blood, vol. 113, no. 10, pp. 2284–2289, 2009.
[13]
R. Aplenc, J. Thompson, P. Han et al., “Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia,” Cancer Research, vol. 65, no. 6, pp. 2482–2487, 2005.
[14]
N. N. Nogueira, J. V. Parente, and S. M. Cozzolino, “Changes in plasma zinc and folic acid concentrations in pregnant adolescents submitted to different supplementation regimens,” Cadernos de Saúde Pública, vol. 19, no. 1, pp. 155–160, 2003.
[15]
C. A. P. da Silva, C. A. P. da Silva, á. N. Atallah, N. Sass, E. T. R. Mendes, and S. Peixoto, “Evaluation of calcium and folic acid supplementation in prenatal care in S？o Paulo,” Sao Paulo Medical Journal, vol. 128, no. 6, pp. 324–327, 2010.
[16]
T. V. Pereira, M. Rudnicki, A. C. Pereira, M. S. Pombo-De-Oliveira, and R. F. Franco, “5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis,” Cancer Epidemiology Biomarkers and Prevention, vol. 15, no. 10, pp. 1956–1963, 2006.
[17]
A. F. Semsei, P. Antal, and C. Szalai, “Strengths and weaknesses of gene association studies in childhood acute lymphoblastic leukemia,” Leukemia Research, vol. 34, no. 3, pp. 269–271, 2010.
[18]
R. F. Franco, B. P. Sim？es, L. G. Tone, S. M. Gabellini, M. A. Zago, and R. P. Falc？o, “The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia,” British Journal of Haematology, vol. 115, no. 3, pp. 616–618, 2001.
[19]
M. Krajinovic, S. Lamothe, D. Labuda et al., “Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia,” Blood, vol. 103, no. 1, pp. 252–257, 2004.
[20]
B. G. Petra, J. Janez, and D. Vita, “Gene—gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children,” Leukemia and Lymphoma, vol. 48, no. 4, pp. 786–792, 2007.
[21]
C. W. Zanrosso, A. Hatagima, M. Emerenciano et al., “The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population,” Leukemia Research, vol. 30, pp. 477–481, 2006.
[22]
I. Costea, A. Moghrabi, C. Laverdiere, A. Graziani, and M. Krajinovic, “Folate cycle gene variants and chemotherapy toxicity in pediatric patients with acute lymphoblastic leukemia,” Haematologica, vol. 91, no. 8, pp. 1113–1116, 2006.
[23]
S. Pakakasama, K. Kanchanakamhaeng, S. Kajanachumpol et al., “Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia,” Annals of Hematology, vol. 86, no. 8, pp. 609–611, 2007.
[24]
N. Shimasaki, T. Mori, C. Torii et al., “Influence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia or lymphoma,” Journal of Pediatric Hematology/Oncology, vol. 30, no. 5, pp. 347–352, 2008.
[25]
L. Huang, W. J. E. Tissing, R. de Jonge, B. D. van Zelst, and R. Pieters, “Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia,” Leukemia, vol. 22, no. 9, pp. 1798–1800, 2008.
[26]
H. Imanishi, N. Okamura, M. Yagi et al., “Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma,” Journal of Human Genetics, vol. 52, no. 2, pp. 166–171, 2007.
[27]
S. Kishi, C. Cheng, D. French et al., “Ancestry and pharmacogenetics of antileukemic drug toxicity,” Blood, vol. 109, no. 10, pp. 4151–4157, 2007.
[28]
B. Faganel Kotnik, I. Grabnar, P. Bohanec Grabar, V. Dol？an, and J. Jazbec, “Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma,” European Journal of Clinical Pharmacology, vol. 67, no. 10, pp. 993–1006, 2011.
[29]
P. Chiusolo, S. Giammarco, S. Bellesi, et al., “The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue,” Cancer Chemotherapy and Pharmacology, vol. 69, no. 3, pp. 691–696, 2012.
[30]
A. M. Kamel, H. S. Moussa, G. T. Ebid, R. R. Bu, and K. G. Bhatia, “Synergistic effect of methyltetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism as risk modifiers of pediatric acute lymphoblastic leukemia,” Journal of the Egyptian National Cancer Institute, vol. 19, no. 2, pp. 96–105, 2007.
[31]
R. K. Thirumaran, A. Gast, T. Flohr et al., “MTHFR genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia,” Blood, vol. 106, no. 7, pp. 2590–2591, 2005.
[32]
D. Oh, K. K. Nam, J. J. Moon et al., “Association of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia,” Anticancer Research, vol. 27, no. 5, pp. 3419–3424, 2007.
