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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 26  |  Issue : 2  |  Page : 138-144

Relationship between MTHFR polymorphism and side effects of high-dose methotrexate in pediatric acute lymphoblastic leukemia


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission17-Feb-2013
Date of Acceptance19-Aug-2013
Date of Web Publication31-Jan-2014

Correspondence Address:
Mahmoud A El-Hawy
Department of Pediatrics, Faculty of Medicine, Menoufia University, Shebin el Kom, 32511 Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.126146

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  Abstract 

Objectives
To study the relationship between plasma methotrexate (MTX) level, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, and the occurrence of complications associated with high-dose methotrexate (HDMTX) in pediatric acute lymphoblastic leukemia (ALL).
Background
ALL is the most common type of cancer in children. Administration of HDMTX, followed by leucovorin rescue is an important component in the treatment of childhood ALL. MTX toxicity mainly includes mucositis, myelosuppression, and hepatic toxicity. MTX toxicity can vary with genetic variability in folate-metabolizing enzymes (e.g. MTHFR).
Patients and methods
A total of 26 ALL children were studied. Clinical assessments, laboratory detection of complete blood count parameters, detection of liver and renal functions before and after HDMTX, detection of MTX level after HDMTX, and PCR (restriction fragment length polymorphism) for the MTHFR polymorphism (C677T and A1298C) were carried out.
Results
The plasma MTX level was found to be related to HDMTX toxicity, especially mucositis. For the C677T MTHFR polymorphism, neutrophil recovery days were higher in TT, followed by CT and CC polymorphism, platelet recovery days were higher in TT, followed by CT and CC polymorphism, and days required for plasma MTX level to decrease to less than 0.1 μmol/l were higher in TT, followed by CT and CC polymorphism. For the A1298C polymorphism, postinfusion platelet count was lower in AA than in AC and CC polymorphism and platelet recovery days were lower in AA than in CC and AC polymorphism. Neutrophil recovery days and days required for plasma MTX level to decrease to less than 0.1 μmol/l were higher in AA, followed by AC and CC polymorphism. For the A1298C polymorphism, AC patients had a significantly higher overall survival than CC and AA patients.
Conclusion
The increase in plasma MTX level after HDMTX might be associated with an increase in the risk for complications. Genotyping of folate polymorphisms might be useful in ALL to optimize MTX therapy, reducing the associated toxicity with possible effects on survival.

Keywords: Acute lymphoblastic leukemia, high-dose methotrexate, MTHFR polymorphism, methotrexate plasma level


How to cite this article:
El Rashedy FH, Ragab SM, Dawood AA, El-Hawy MA. Relationship between MTHFR polymorphism and side effects of high-dose methotrexate in pediatric acute lymphoblastic leukemia. Menoufia Med J 2013;26:138-44

How to cite this URL:
El Rashedy FH, Ragab SM, Dawood AA, El-Hawy MA. Relationship between MTHFR polymorphism and side effects of high-dose methotrexate in pediatric acute lymphoblastic leukemia. Menoufia Med J [serial online] 2013 [cited 2017 Oct 22];26:138-44. Available from: http://www.mmj.eg.net/text.asp?2013/26/2/138/126146


  Introduction Top


Acute leukemia is the most common type of cancer in children and it comprises ˜30% of all childhood malignancies, with acute lymphoblastic leukemia (ALL) being five times more common than acute myeloid leukemia [1] . ALL is an aggressive neoplasm of the blood and bone marrow. It is a heterogeneous disease in which many genetic lesions result in the development of multiple biological subtypes. This type of cancer usually worsens rapidly if it is not treated [2] . The antifolate methotrexate (MTX), by blocking methylenetetrahydrofolate reductase (MTHFR), interrupts folate metabolism by inhibiting the synthesis of dTMP needed for DNA replication. MTX is an important component of consolidation and maintenance therapy in childhood ALL. MTX toxicity mainly includes mucositis, myelosuppression, and hepatic toxicity. MTX toxicity can vary with genetic variability in folate-metabolizing enzymes [3] .

Consequently, patients with decreased MTHFR activity are at an increased risk of MTX-related toxicity [4] . The combination of high-dose methotrexate (HDMTX) with extended intrathecal MTX has been found to be effective central nervous system prophylaxis in established ALL protocols. The rationale for using HDMTX is based on the principles of dose-dependent increased formation of MTX polyglutamates, the potential to overcome mechanisms of MTX resistance related to impaired cellular drug uptake, and the achievement of cytotoxic drug concentrations in the cerebrospinal fluid [5] .

MTHFR is a critical enzyme in one-carbon metabolism. MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which is the predominant circulating form of folate and serves as the carbon donor for the remethylation of homocysteine to methionine. The MTHFR gene is localized on chromosome 1p36.3 [6] . Two common polymorphisms (variants) have been described in the MTHFR gene, which are single-nucleotide substitution resulting in amino acid changes: (i) the MTHFR C677T (exon 4 at codon 222), which is a C>T substitution at position 677 resulting in an alanine to valine substitution, and (ii) the A1298C (exon 7 at codon 429), causing a glutamate to alanine (A>C) substitution. Both of these polymorphisms have impairment in the enzyme activity. The C677T and A1298C alleles have been found to result in decreased enzyme activity, leading to an imbalance in plasma folate concentration [7] .


  Patients and methods Top


After approval from the local institutional ethical committee of Menoufia University Hospital, 26 pediatric ALL patients who were admitted to the Hematology and Oncology Unit, Pediatric Department, Menoufia University Hospitals, and received the St. Jude total VX chemotherapy protocol were included.

Study design

This is a follow-up study, which included 26 pediatric patients with ALL (11 boys and 15 girls). Their ages ranged from 2 to 15 years. Patients were subjected to the following: (i) at the consolidation phase of chemotherapy before infusion of each HDMTX: (a) thorough clinical examination with a focus on the absence of oral mucositis, and (b) complete blood count [hemoglobin (Hb), white blood cells (WBCs), absolute neutrophil count (ANC), and platelets], liver function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin], and kidney function tests [urea, creatinine, and glomerular filtration rate (GFR)]. GFR was estimated using the Schwartz formula. (ii) After infusion of each HDMTX: (a) thorough clinical examination by daily assessment for the detection of mucositis, vomiting, diarrhea, or fever. Grading of mucositis, vomiting, and diarrhea were registered at day 7 after the start of HDMTX using the WHO grading scale. (b) Assessment of MTX level in serum at 42 h after the start of infusion and repeated every 24 h until the level decreased to less than 0.10 μmol/l, and complete blood count (Hb level, WBCs, ANC, and platelets) at day 7 after the start of HDMTX, liver function tests, and renal function tests.

Laboratory analysis of MTHFR C677>T and A1298>C genotypes

DNA was extracted using QIAamp DNA Blood Mini Kits (Qiagen, Hilden, Germany). PCR amplification and enzymatic digestion of the products were performed.

For the MTHFR C677T polymorphism

Genomic DNA (0.5-2 μg) was amplified with each of forward primer 5′-TGAAGGAGAAGGTGTCTGCGGGA-3′ and a reverse primer 5′-AGGACGGTGCGGT GAGAGTG-3′ (supplied by biosynthesis). PCR was performed with a Biometra thermoblock (Biometra, Goettingen, Germany) using Perkin Elmer Thermal Cycler 2400 (Perkin Elmer, Waltham, Massachusetts, USA) under the standard conditions: an initial denaturation (5 min at 94°C), denaturation (1 min at 95°C), annealing (1 min at 59°C), and extension (0.25 min at 72), and number of cycles: 30 with final extension (10 min at 72°C).

After amplification, the PCR products were digested with restriction endonuclease HinfI and the products were run in a 2% agarose gel electrophoresis for 30 min and stained with ethidium bromide, and the bands were visualized under ultraviolet light. Wild-type CC showed a single band at 198 bp. For heterozygous CT three bands of 198, 175, and 23 bp were observed. The homozygous TT had two bands of 175 and 23 bp.

For the MTHFR A1298>C polymorphism

Genomic DNA (0.5-2 μg) was amplified with each of forward primer 5′-CTTTGGGGA GCTGAAGGACTACTAC-3′ and reverse primer 5′-CACTTTGTGACCATT CCGGTTTG-3′ using an initial denaturation (5 min at 94°C), denaturation (1 min at 95°C), annealing (1 min at 59°C), and extension (15 s at 72°C), number of cycles 30 and final extension (0.25 min at 72° C), using Perkin Elmer Thermal Cycler 2400.

After amplification, the PCR products were digested with restriction endonuclease MboII and the products were run in a 2% agarose gel electrophoresis for 30 min and stained with ethidium bromide, and the bands were visualized under ultraviolet light. Wild-type AA produced fragments of 56, 30, 31, 28, and 18 bp. Heterozygous AC produced fragments of 84, 56, 30, 31, 28, and 18 bp, whereas homozygous CC produced 84, 30, 31, and 18 bp fragments.


  Results Top


The present study included 26 ALL patients aged 2-15 years (mean 6±4years) including 11 boys and 15 girls. Their immunophenotypes were pre-B-lineage in 23 (88.5%) and T-lineage in three (11.5%). Twelve patients (46.2%) were classified as low risk, whereas 14 (53.8%) were classified as standard risk according to the protocol risk stratification criteria.

With respect to the distribution of C677T and A1298C MTHFR polymorphism among the patients studied, 14 (53.8%) had CT (heterozygous mutant allele), whereas seven (26.9%) had TT (homozygous mutant allele) and five (19.2%) had CC (wild homozygous allele). With respect to the A1298C polymorphism, 18 patients (69.2%) had AC (heterozygous mutant allele), whereas five (19.2%) had AA (wild homozygous allele) and three (11.5%) had CC (homozygous mutant allele). The allele frequencies for C and T alleles of MTHFR C677T were 46 and 54%, respectively, and the allele frequencies for C and A alleles of MTHFR A1298C were 46 and 54%, respectively [Table 1].
Table 1: Distribution of C677T and A1298C MTHFR polymorphisms among the patients studied

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The plasma MTX level at 42 h after infusion was significantly correlated with 66 h plasma MTX level with respect to days required for plasma MTX level to decrease to less than 0.1 μmol/l, total Ca leucovorin dose used postinfusion until the plasma MTX level reaches less than 0.1 μmol/l, postinfusion symptom days, mucositis, postinfusion serum creatinine level, and postinfusion direct bilirubin level. However, there was no significant correlation with neutrophil recovery days, platelet recovery days, vomiting, diarrhea, postinfusion Hb level, red blood cell (RBC) count, WBC count, neutrophil count, platelets count, AST level, ALT level, total bilirubin level, or estimated GFR.

The plasma MTX level at 66 h after infusion was significantly correlated with 42 h plasma MTX level to the total Ca leucovorin dose used after infusion until plasma MTX level decreased to less than 0.1 μmol/l, postinfusion symptom days, mucositis, and days required for plasma MTX level to decrease to less than 0.1 μmol/l. However, there was no significant correlation with neutrophil recovery days, platelet recovery days, vomiting, diarrhea, postinfusion Hb level, RBC count, WBC count, neutrophil count, platelets count, AST level, ALT level, total bilirubin level, direct bilirubin level, serum creatinine level, and estimated GFR [Table 2].
Table 2: Correlations between the mean plasma methotrexate levels and the mean postdose parameters

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Neutrophil recovery days (considered the duration in days until ANC reached 500/mm 3 ), platelet recovery days (considered as the duration in days until platelets count reached 50 × 10 3 /mm 3 ), and days required for plasma MTX level to decrease to less than 0.1 μmol/l were significantly higher in homozygous mutant (TT) patients compared with other patients, without a significant difference between them with respect to postinfusion neutrophil count, platelet count, 42 h plasma MTX level, 66 h plasma MTX level, AST, ALT, serum creatinine, estimated GFR, or postinfusion symptoms days (oral mucositis, vomiting, diarrhea, and fever if present) [Table 3].
Table 3: Comparison between C677T polymorphism categories with respect to plasma methotrexate level and postdose effects

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Patients with a wild homozygous (AA) allele had significantly longer neutrophil recovery days, platelets recovery days, days required to MTX level to decrease to less 0.1 μmol/l, and had lower postinfusion platelet count compared with heterozygous mutant (AC) polymorphism and homozygous mutant (CC) polymorphism patients [Table 4].
Table 4: Comparison between A1298C polymorphism categories with respect to plasma methotrexate level and postdose effects

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Severe vomiting occurred more frequently in patients with the homozygous mutant (TT) polymorphism compared with wild homozygous (CC) allele and heterozygous mutant (CT) patients. Whereas no significant difference between them with respect to the occurrence of severe oral mucositis was found, severe vomiting and severe mucositis occurred more frequently in patients with the wild homozygous (AA) allele polymorphism compared with heterozygous mutant allele (AC) allele and homozygous mutant (CC) allele patients [Table 5].
Table 5: Comparison between C677T and A1298C polymorphism categories with respect to gastrointestinal tract complications

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The overall survival in MTHFR C677T was determined using the Kaplan-Meier curve [Figure 1]; it was found that CT (heterozygous mutant allele) patients had better survival but there was no significant difference in overall survival between these patients and CC (wild homozygous allele) or TT (homozygous mutant allele) patients (P> 0.05).
Figure 1:

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The Kaplan-Meier curve [Figure 2] showed that patients with the MTHFR A1298C heterozygous mutant (AC) allele had significantly better overall survival compared with patients with the wild homozygous (AA) allele or the homozygous mutant (CC) allele (P< 0.05).
Figure 2:

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  Discussion Top


Recently, the influence of polymorphisms of different genes involved in the metabolism of chemotherapeutic agents including the MTHFR gene polymorphism has been studied, especially in childhood ALL [8] . Two single-nucleotide polymorphisms in the MTHFR gene, C677T and A1298C, affect MTHFR activity [9] .

In this study, we investigated whether there is a relationship between MTHFR gene polymorphisms (C677T and A1289C) and plasma MTX level, and its complications in 26 pediatric patients with ALL who received the St. Jude Children Research Hospital total XV therapy protocol.

This study showed that 53.8% of patients had the MTHFR C677T heterozygous mutant (CT) polymorphism, whereas 26.9% had the homozygous mutant (TT) polymorphism and 19.2% had the wild homozygous (CC) polymorphism. These results are not consistent with those of El Khodary et al. [10] , who studied 40 Egyptian pediatric ALL patients and found that the MTHFR C677T polymorphic distributions were 55, 35, and 10% for CC, CT, and TT genotypes, respectively. Also, Tantawy et al. [3] studied 40 Egyptian pediatric ALL patients and found that their MTHFR C677T polymorphic distributions were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively.

In Iran, Atashrazm et al. [11] studied 103 pediatric ALL patients and found that their MTHFR C677T polymorphic distributions were 65.05, 33.0, and 1.95% for CC, CT, and TT genotypes, respectively.

Also, Nikbakht et al. [12] studied 125 Indian pediatric ALL patients and found that their MTHFR C677T polymorphic distributions were 49.6, 43.2, and 7.2% for CT, CC, and TT genotypes, respectively.

This difference might be because of geographic and ethnic distributions and the number of patients included in each study.

With respect to the A1298C polymorphism in our study, 69.2% had the heterozygous mutant (AC) polymorphism, whereas 19.2% had the wild homozygous (AA) polymorphism and 11.5% had the homozygous mutant (CC) polymorphism. These results are consistent with those of Atashrazm et al. [11] , who found that the MTHFR A1298C polymorphic distributions were 58.3, 30.1, and 11.6% for AC, AA, and CC genotypes, respectively. Also, Nikbakht et al. [12] found that the MTHFR A1298C polymorphic distributions were 52, 41.6, and 6.4% for AC, AA, and CC genotypes, respectively.

However, Tantawy et al. [3] found that, for the MTHFR A1298>C, distributions of the polymorphic alleles were 40, 35, and 25% for AA, AC, and CC genotypes, respectively.

In this study, the results showed that the MTHFR C667T homozygous mutant (TT) genotype had significantly longer neutrophil recovery days, longer platelets recovery days, longer duration for plasma MTX level required to decrease to less than 0.1 μmol/l, and occurrence of severe vomiting (>grade 2) compared with heterozygous mutant (CT) and homozygous wild (CC) genotypes.

The previous results are in contrast to those of Kantar et al. [13] , who studied 37 Turkish children with ALL and non-Hodgkin lymphoma and concluded that patients with the MTHFR polymorphism for C677T (CT and TT) had significantly higher MTX levels at 24 h, and these genotypes did not seem to cause toxicity.

However, El Khodary et al. [10] found that MTX therapy was significantly associated with toxicity signs and delayed MTX elimination in TT genotype.

Also, Tantawy et al. [3] found that the TT genotype was significantly associated with longer duration of neutropenia.

In this study, the results showed that the MTHFR A1298C wild homozygous (AA) genotype had significantly lower postinfusion platelet count, longer neutrophils recovery days, longer platelets recovery days and required longer duration for plasma MTX level to decrease to less than 0.1 μmol/l, and occurrence of severe vomiting and mucositis (>grade 2) than heterozygous mutant AC and homozygous mutant (CC) genotypes.

These results are in agreement with those of Huang et al. [8] , who studied 81 Dutch children with ALL and found that the WBC count decreased for the wild (AA) genotype, and the MTHFR 1298 AC/CC genotypes were associated with a decrease in hematological toxicity (>2-fold less blood transfusions and a more rapid recovery of leukocyte count).

The A1298C polymorphism (AC and CC) results in a glutamate to alanine substitution and reduced enzyme activity. Reduced conversion of 5, 10-methylenetetrahyd rofolate into 5-methyltetrahydrofolate may lead to more substrate for thymidylate synthase and thereby to more DNA synthesis, which might result in lesser side effects. However, it might also result in less antileukemic activity [8] .

Also, Liu et al. [14] found that the AA genotype was associated with more MTX side effects than AC and CT genotypes.

In contrast, Tantawy et al. [3] found no significant relation between the MTHFR A1298C polymorphism and the risks of therapy-induced complications.

Also, Kantar et al. [13] found that patients with the MTHFR polymorphism for A1298C (AC and CC) had significantly higher MTX levels at 48 h, and had more anemia, thrombocytopenia, elevated AST levels, and frequent febrile neutropenic episodes.

Yang et al. [15] reviewed 14 studies, with all studies investigating the MTHFR C677T polymorphism, with nine of them investigated only the MTHFR A1298C polymorphism, and suggested that the MTHFR C677T polymorphism TT/CT versus CC was associated with a significantly increased risk of MTX-induced toxicity, specifically gastrointestinal toxicity. Also, Liu et al. [14] studied 44 Chinese ALL pediatric patients and found that the TT genotype was associated with more MTX side effects than CC and CT genotypes.

The Kaplan-Meier curve [Figure 1] showed that C677T heterozygous mutant (CT) patients had the highest overall survival, followed by homozygous wild (CC) and homozygous mutant (TT) patients, but with no statistically significant difference between them.

These results are in partial agreement with those of El Khodary et al. [10] and Tantawy et al. [3] , who found that CC patients had the highest relapse-free survival and the highest overall survival, followed by CT and TT patients, with a statistically significant difference between them.

In contrast, De Dues et al. [16] studied 126 Brazilian pediatric ALL patients and found that TT patients had better survival, followed by CC and CT patients, with a statistically significant difference between them.

The Kaplan-Meier curve [Figure 2] showed that A1298C heterozygous mutant (AC) patients had significantly the highest overall survival, followed by homozygous mutant (CC) and wild homozygous (AA) patients.

These results are in partial agreement with those of De Dues et al. [16] . They found that CC patients had better survival, followed by AA and AC, with a statistically significant difference between them.

Tantawy et al. [3] concluded that the MTHFR A1298C variant alleles were not associated with a significantly altered risk of relapse or survival.


  Conclusion Top


From this study, it can be concluded that an increase in the plasma MTX level after HDMTX might be associated with an increase in the risk for complications. Also, genotyping of MTHFR A1298C polymorphisms might be useful in pediatric patients with ALL to predict the severity of MTX-associated toxicity with possible effects on survival.


  Acknowledgements Top


Conflicts of interest

None declared.

 
  References Top

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3.Tantawy AA, El-Bostany EA, Adly AA, Abou El Asrar M, El-Ghouroury EA, Abdulghaffar EE. Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2010; 21 :28-34.  Back to cited text no. 3
    
4.D′Angelo V, Ramaglia M, Iannotta A, Crisci S, Indolfi P, Francese M, et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 2011; 68 :1339-1346.  Back to cited text no. 4
    
5.Kapoor G, Sinha R, Abedin S. Experience with high dose methotrexate therapy in childhood acute lymphoblastic leukemia in a tertiary care cancer centre of a developing country. Pediatr Blood Cancer 2012; 59 :448-453.  Back to cited text no. 5
    
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7.Zintzaras E, Doxani C, Rodopoulou P, Bakalos G, Ziogas DC, Ziakas P, Voulgarelis M. Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: a synthesis of genetic association studies. Cancer Epidemiol 2012; 36 :169-176.  Back to cited text no. 7
    
8.Huang L, Tissing WJ, de Jonge R, van Zelst BD, Pieters R. Polymorphisms in folate-related genes: association with side effects of high-dose methotrexat childhood acute lymphoblastic leukemia. Leukemia 2008; 22 :1798-1800.  Back to cited text no. 8
    
9.Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 2012; 23 :1038-1044.  Back to cited text no. 9
    
10.El-Khodary N, El-Haggar S, Eid M, Ebeid E. Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia. Med Oncol 2012; 29 :2053-2062.  Back to cited text no. 10
    
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12.Nikbakht M, MalekZadeh K, Kumar Jha A, Askari M, Marwaha R, Kaul D, Kaur J. Polymorphisms of MTHFR and MTR genes are not related to susceptibility to childhood ALL in north India. Exp Oncol 2012; 34 :43-48.  Back to cited text no. 12
    
13.Kantar M, Kosova B, Cetingul N, Gumus S, Toroslu E, Zafer N, et al. Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma 2009; 50 :912-917.  Back to cited text no. 13
    
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16.De Deus D, de Lima E, Seabra Silva R, Leite E, Cartaxo Muniz M. Influence of methylenetetrahydrofolate reductase C677T, A1298C, and G80A polymorphisms on the survival of pediatric patients with acute lymphoblastic leukemia. Leuk Res Treat 2012; 2012 :1-6.  Back to cited text no. 16
    


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    Tables

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