Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia
Ilan J. N. Koppen, Frederik J. R. Hermans, Gertjan J. L. Kaspers,
Gertjan J. L. Kaspers
Department of Paediatric Oncology/Haematology, VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorIlan J. N. Koppen, Frederik J. R. Hermans, Gertjan J. L. Kaspers,
Gertjan J. L. Kaspers
Department of Paediatric Oncology/Haematology, VU University Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorProfessor Dr Gertjan J. L. Kaspers, Department of Paediatrics, Division of Oncology/Haematology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. E-mail: [email protected]
Summary
Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate-related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate-related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age-defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non-Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms.
References
- Alcasabas, P., Ravindranath, Y., Goyette, G., Haller, A., Del Rosario, L., Lesaca-Medina, M.Y., Darga, L., Ostrea, E.M.J., Taub, J.W. & Everson, R.B. (2008) 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children. Pediatric Blood and Cancer, 51, 178–182.
- Alessio, A.C., Hoehr, N.F., Siqueira, L.H., Bydlowski, S.P. & Nnichino-Bizzacchi, J.M. (2007) Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children. Thrombosis Research, 119, 571–577.
- Chatzidakis, K., Goulas, A., Thanassiadou-Piperopoulou, F., Fidani, L., Koliouskas, D. & Mirtsou, V. (2006) Methylenetetrahydrofolate reductase C677T polymorphism: association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients. Pediatric Blood and Cancer, 47, 147–151.
- Chiusolo, P., Reddiconto, G., Cimino, G., Sica, S., Fiorini, A., Farina, G., Vitale, A., Sora, F., Laurenti, L., Bartolozzi, F., Fazi, P., Mandelli, F. & Leone, G. (2004) Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukemia pathogenesis in the Italian population. Haematologica, 89, 139–144.
- Cortese, C. & Motti, C. (2001) MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutrition, 4, 493–497.
- Franco, R.F., Simoes, B.P., Tone, L.G., Gabellini, S.M., Zago, M.A. & Falcao, R.P. (2001) The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia. British Journal of Haematology, 115, 616–618.
- Gast, A., Bermejo, J.L., Flohr, T., Stanulla, M., Burwinkel, B., Schrappe, M., Bartram, C.R., Hemminki, K. & Kumar, R. (2007) Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study. Leukemia, 21, 320–325.
- Gemmati, D., Ongaro, A., Scapoli, G.L., La Porta, M., Tognazzo, S., Serino, M.L., Di Bona, E., Rodeghiero, F., Gilli, G., Reverberi, R., Caruso, A., Pasello, M., Pellati, A. & De Mattei, M. (2004) Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiology Biomarkers & Prevention, 13, 787–794.
- Giovannetti, E., Ugrasena, D.G., Supriyadi, E., Vroling, L., Azzarello, A., De Lange, D., Peters, G.J., Veerman, A.J.P. & Cloos, J. (2008) Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia. Leukemia Research, 32, 19–24.
- Greaves, M.F. (1997) Aetiology of acute leukaemia. The Lancet, 349, 344–349.
- De Jonge, R., Tissing, W.J.E., Hooijberg, J.H., Jansen, G., Kaspers, G.J.L., Lindemans, J., Peters, G.J. & Pieters, R. (2009) Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood, 113, 2284–2289.
- Kamel, A.M., Moussa, H.S., Ebid, G.T., Bu, R.R. & Bhatia, K.G. (2007) Synergistic Effect of Methyltetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphism as Risk Modifiers of Pediatric Acute Lymphoblastic Leukemia Using Tissue Microarray. Journal of the Egyptian National Cancer Institute, 19, 96–105.
- Karathanasis, N.V., Choumerianou, D.M. & Kalmanti, M. (2009) Gene polymorphisms in childhood ALL. Pediatric Blood and Cancer, 52, 318–323.
- Kim, Y.I. (2000) Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutrition Reviews, 58, 205–209.
- Kim, Y.I. (2004a) Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environmental and Molecular Mutagenesis, 44, 10–25.
- Kim, Y.I. (2004b) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiology Biomarkers & Prevention, 13, 511–519.
- Kim, Y.I. (2005) Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. Journal of Nutrition, 135, 2703–2709.
- Kim, D.H. (2007) The interactive effect of methyl-group diet and polymorphism of methylenetetrahydrofolate reductase on the risk of colorectal cancer. Mutation Research, 622, 14–18.
- Kim, H.N., Kim, Y.K., Lee, I.K., Yang, D.H., Lee, J.J., Shin, M.H., Park, K.S., Choi, J.S., Park, M.R., Jo, D.Y., Won, J.H., Kwak, J.Y. & Kim, H.J. (2009) Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leukemia Research, 33, 82–87.
- Krajinovic, M., Lamothe, S., Labuda, D., Lemieux-Blanchard, E., Theoret, Y., Moghrabi, A. & Sinnett, D. (2004a) Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood, 103, 252–257.
- Krajinovic, M., Lemieux-Blanchard, E., Chiasson, S., Primeau, M., Costea, I. & Moghrabi, A. (2004b) Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. The Pharmacogenomics Journal, 4, 66–72.
- Nakai, K., Itoh, C., Nakai, K., Habano, W. & Gurwitz, D. (2001) Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD. American Journal of Cardiovascular Drugs, 1, 353–361.
- Oh, D., Kim, N.K., Jang, M.J., Kim, H.C., Lee, J.H., Lee, J.A., Ahn, M.J., Kim, C.S., Kim, H.S., Park, S., Chio, H.S. & Min, Y.H. (2007) Association of the 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia. Anticancer Research, 27, 3419–3424.
- Oliveira, E., Alves, S., Quental, S., Ferreira, F., Norton, L., Costa, V., Amorim, A. & Prata, M.J. (2005) The MTHFR C677T and A1298C polymorphisms and susceptibility to childhood acute lymphoblastic leukemia in Portugal. Journal of Pediatric Hematology/Oncology, 27, 425–429.
- Patterson, D. (2008) Folate metabolism and the risk of Down syndrome. Down Syndrome Research and Practice, 12, 93–97.
- Poole, C., Greenland, S., Luetters, C., Kelsey, J.L. & Mezei, G. (2006) Socioeconomic status and childhood leukaemia: a review. International Journal of Epidemiology, 35, 370–384.
- Rady, P.L., Szucs, S., Matalon, R.K., Grady, J., Hudnall, S.D., Kellner, L.H. & Nitowsky, H. (2001) Genetic polymorphism (G80A) of reduced folate carrier gene in ethnic populations. Molecular Genetics and Metabolism, 73, 285–286.
- Reeves, S.G., Meldrum, C., Groombridge, C., Spigelman, A.D., Suchy, J., Kurzawski, G., Lubinski, J., McElduff, P. & Scott, R.J. (2009) MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. The European Journal of Human Genetics, 17, 629–635.
- Ribeiro, K.B., Buffler, P.A. & Metayer, C. (2008) Socioeconomic status and childhood acute lymphocytic leukemia incidence in Sao Paulo, Brazil. The International Journal of Cancer, 123, 1907–1912.
- Robien, K. & Ulrich, C.M. (2003) 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. American Journal of Epidemiology, 157, 571–582.
- Roessler, M., Rollinger, W., Palme, S., Hagmann, M.L., Berndt, P., Engel, A.M., Schneidinger, B., Pfeffer, M., Andres, H., Karl, J., Bodenmuller, H., Ruschoff, J., Henkel, T., Rohr, G., Rossol, S., Rosch, W., Langen, H., Zolg, W. & Tacke, M. (2005) Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clinical Cancer Research, 11, 6550–6557.
- Salerno, P., Bianchi, F., Pierini, A., Baldi, F., Carbone, P., Mantovani, A. & Taruscio, D. (2008) Folic acid and congenital malformation: scientific evidence and public health strategies. Annali di Igiene, 20, 519–530.
- Schnakenberg, E., Mehles, A., Cario, G., Rehe, K., Seidemann, K., Schlegelberger, B., Elsner, H.A., Welte, K.H., Schrappe, M. & Stanulla, M. (2005) Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population. BMC Medical Genetics, 6, 23.
- Shah, S.J., Taub, J.W., Witt, T.L., Pollock, B.H., Ding, B.C., Moore, D.S., Amylon, M., Pullen, J., Ravindranath, Y. & Matherly, L.H. (2001) Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia. British Journal of Haematology, 113, 746–756.
- Skibola, C.F., Smith, M.T., Kane, E., Roman, E., Rollinson, S., Cartwright, R.A. & Morgan, G. (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proceedings of the National Academy of Sciences of the United States of America, 96, 12810–12815.
- Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A. & Morgan, G.J. (2002) Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood, 99, 3786–3791.
- Smith, A., Roman, E., Simpson, J., Ansell, P., Fear, N.T. & Eden, T. (2006) Childhood leukaemia and socioeconomic status: fact or artefact? A report from the United Kingdom childhood cancer study (UKCCS). International Journal of Epidemiology, 35, 1504–1513.
- Sohn, K.J., Jang, H., Campan, M., Weisenberger, D.J., Dickhout, J., Wang, Y.C., Cho, R.C., Yates, Z., Lucock, M., Chiang, E.P., Austin, R.C., Choi, S.W., Laird, P.W. & Kim, Y.I. (2009) The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification. The International Journal of Cancer, 124, 1999–2005.
- Thirumaran, R.K., Gast, A., Flohr, T., Burwinkel, B., Bartram, C., Hemminki, K. & Kumar, R. (2005) MTHFR genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia. Blood, 106, 2590–2591.
- Vrooman, L.M. & Silverman, L.B. (2009) Childhood acute lymphoblastic leukemia: update on prognostic factors. Current Opinion in Pediatrics, 21, 1–8.
- Wiemels, J.L., Smith, R.N., Taylor, G.M., Eden, O.B., Alexander, F.E. & Greaves, M.F. (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proceedings of the National Academy of Sciences of the United States of America, 98, 4004–4009.
- Xue, H.C., Wang, J.M., Xu, B., Guo, G.P., Hua, Z.L., Zhou, Q., Zhu, Z.H., Ma, Z.K. & Gao, J. (2008) Correlation of aberrant methylation of MGMT gene to MTHFR C677T genetic polymorphisms in esophageal squamous cell carcinoma. Ai Zheng., 27, 1256–1262.
- Zanrosso, C.W., Hatagima, A., Emerenciano, M., Ramos, F., Figueiredo, A., Felix, T.M., Segal, S.L., Guigliani, R., Muniz, M.T.C. & Pombo-de-Oliveira, M.S. (2006) The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population. Leukemia Research, 30, 477–481.
Citing Literature
