|Year : 2012 | Volume
| Issue : 3 | Page : 355-360
Methylenetetrahydrofolate reductase gene polymorphisms (677C > T and 1298A > C) in Egyptian patients with non-hodgkin lymphoma
Aml S Nasr1, Rania M Sami1, Noha Y Ibrahim2
1 Department of Clinical Pathology, Kasr El Eini School of Medicine, Cairo University, Egypt
2 Department of Nuclear Medicine and Oncology, Kasr El Eini School of Medicine, Cairo University, Egypt
|Date of Web Publication||17-Nov-2012|
Aml S Nasr
Department of Clinical Pathology, Kasr El Eini School of Medicine, Cairo University
Background: Folate metabolism plays an essential role in Deoxyribonucleic acid (DNA) synthesis and methylation processes. Deviations in the flux of the folate may affect the susceptibility to various cancers including lymphoma.
Aim: The aim of this study was to investigate the genetic polymorphisms in 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C/T and 1298A/C) and to evaluate its associations with the risk of Non Hodgkin lymphoma.
Materials and Methods: The study included 50 patients with diffuse large B cell lymphoma (DLBCL) as well as 50 age matched apparently healthy volunteers (as control). All the subjects included in the study were genotyped for the detection of the MTHFR gene polymorphisms (677C > T and 1298A > C) by using restriction fragment length polymorphism (PCR-RFLP).
Results: There were highly statistically significant differences between the 2 groups with respect to results of PCR-RFLP for MTHFR 677C→T polymorphism for CC genotype (P value = 0.001), statistically significant differences for CT (P value = 0.048) and TT (P value = 0.038) genotypes; however, no statistically significant differences regarding CC/CT or TT/CT alleles (P value = 0.052). Also, there were highly statistically significant differences between the patient and control groups with regards to the results of MTHFR1298 A/C polymorphism for the AA, AC genotypes as well as the AA/AC and CC/AC alleles (P value < 0.0001), and statistically significant difference regarding CC genotype (P value 0.0192).
Conclusion: In conclusion, this study demonstrated a significant association between the MTHFR polymorphisms and the risk of DLBCL. Thus the study could support that folate intake together with the genetic basis may help in modifying the risk to lymphoma.
Keywords: Methylenetetrahydrofolate reductase, methylenetetrahydrofolate reductase gene polymorphisms, non Hodgkin lymphoma, promoter polymorphisms, restriction fragment length polymorphism, risk
|How to cite this article:|
Nasr AS, Sami RM, Ibrahim NY. Methylenetetrahydrofolate reductase gene polymorphisms (677C > T and 1298A > C) in Egyptian patients with non-hodgkin lymphoma. J Can Res Ther 2012;8:355-60
|How to cite this URL:|
Nasr AS, Sami RM, Ibrahim NY. Methylenetetrahydrofolate reductase gene polymorphisms (677C > T and 1298A > C) in Egyptian patients with non-hodgkin lymphoma. J Can Res Ther [serial online] 2012 [cited 2013 Dec 6];8:355-60. Available from: http://www.cancerjournal.net/text.asp?2012/8/3/355/103512
| > Introduction|| |
Non-Hodgkin's lymphoma (NHL) is a heterogeneous group of malignancies of the B- and T-cells that involves their uncontrolled clonal expansion in the periphery. B cell lymphomas make up the majority of the cases and, of these, diffuse large B-cell lymphoma (DLCL) and follicular lymphoma (FL) are the two major subtypes.  In 2007, NHL accounted for approximately 59,000 newly diagnosed cases and 19,000 deaths in the United States and over 300,000 cases and 172,000 deaths worldwide.  A number of case-control association studies have examined the role of genetic polymorphisms in the risk of lymphoma and several genetic variants have been identified as the potential susceptibility loci. These studies may serve to identify at the risk populations, and to further clarify the important disease mechanisms. 
Folate and methionine metabolism plays an essential role in both the Deoxyribonucleic acid (DNA) synthesis and methylation. At least 30 enzymes have been identified in the folate pathway.  Several single nucleotide polymorphisms (SNP) in the genes encoding these enzymes, decrease or increase the enzyme activity,  and have been associated with the risk of adult and childhood acute lymphocytic leukemia (ALL),  non-Hodgkin's lymphoma,  colorectal cancer,  and endometrial cancer.  The methylenetetrahydrofolate reductase (MTHFR) gene, which is located on chromosome 1p36,  is reported to have 2 polymorphisms involving nucleotides 677 (C→T; alanine→valine) and 1298 (A→C; glutamate→alanine). Both polymorphisms lead to reduced MTHFR activity,  and result in the accumulation of 5, 10-methylene tetrahydrofolate (THF). This in turn reduces the chance for the misincorporation of uracil into DNA, a cause of double-strand breaks during uracil excision repair. 
Neural tube defect,  coronary artery disease,  cerebrovascular disease,  venous thrombotic disease  and colorectal cancer,  are reported to be associated with these polymorphisms. However, few studies have examined the genetic variations in folate transport and metabolism to be associated with a risk of NHL. The aim of the study was to analyze (MTHFR677 C/T, MTHFR1298 A/C) polymorphisms that may alter the risk of chromosomal translocations and DNA methylation patterns, and therefore the susceptibility to NHL.
| > Materials and Methods|| |
The current study was carried out on 50 patients diagnosed as having diffuse large B cell lymphoma (DLBCL). The patients were chosen in the period between April 2009 and November 2010 among cases referred to nuclear medicine and oncology unit after taking their written informed consent and having the local ethical committee approval. The sample size was calculated. The extent of the disease was categorized according to the Ann Arbor classification,  and International Prognostic Index (IPI).  They were 27 males and 23 females patients. Their age ranged between 22 to 73 years. Fifty age matched apparently healthy adults were enrolled as control group after taking their written informed consent. They were 19 males and 31 females. Their ages ranged between 18 and 77 years. All the patients and controls were analyzed for clinical and laboratory findings, including full history taking, clinical examination, routine laboratory investigations, serum Lactate dehydrogenase (LDH), beta 2 microglobulin and abdominal ultrasound for detection of organomegaly and lymphadenopathy. The patients were subjected to immunophenotyping to rule out other lymphoproliferative disorders, lymph node biopsy for diagnosis of non Hodgkin lymphoma, bone marrow biopsy and immunohistochemistry for staging, and computerized tomography (CT) abdomen and pelvis for proper diagnosis and staging.
Genotyping for detection of MTHFR gene polymorphisms (MTHFR677 C/T, MTHFR1298 A/C) by restriction fragment length polymorphism (RFLP) was performed for both patients and controls. Detection of (MTHFR677 C/T, MTHFR1298 A/C) polymorphisms by PCR-RFLP: Three ml of blood was withdrawn from all the subjects included in the study in a sterile ethelenediaminetetraacetic acid (EDTA)) vacutainer. DNA was extracted from the whole blood using a DNA extraction kit, (QIAamp Blood Kit (Cat. No. 51106; Qiagen Inc., Valencia, CA), and following the manufacturer's instructions.
MTHFR 677C→T polymorphism
The method described by Frosst et al.,  was used for detection of the 677 C→T polymorphism. A length of 198 base pairs on exon 4 of the MTHFR gene was amplified using 5′ TGA AGG AGA AGG TGT CTG CGG GA 3′ as the forward primer and 5′ AGG ACG GTG CGG TGA GAG TG 3′ as the reverse primer. The C to T polymorphism at codon 677 introduces a restriction site for enzyme Hinf 1. The polymerase chain reaction (PCR) was carried out in a total volume of 25 μL containing about 200 ng/ ml DNA, 2 μl of 2.5 mM of each of the Deoxyribonucleotide triphosphate (dNTP's), 0.5 μl of 25 mM magnesium chloride (MgCl 2 ), 10 pmol of both primers and 0.5 U Taq polymerase. PCR cycling conditions were as follows: an initial denaturation step at 94°C for 5 minutes; and, 30 cycles of the following: 94°C for 1 minute, 57°C for 1 minute, and 72°C for 15 seconds. This was followed by a 10 minute extension at 72°C. Restriction digestion with Hinf 1 (Fermentas, INC, USA) was carried out on 2 μl buffer, 1 μl Hinf 1, and 8 μl of PCR amplicons incubated at 37°C for 4 to 6 hours. The digested fragments were separated on 2.5% agarose gel electrophoresis stained with ethidium bromide. The electrophoretic pattern was visualized under ultraviolet (UV) light and then photographed using a Polaroid camera with a red orange filter. Wild type (677CC) showed a single band at 198 bp. The presence of the 'T' allele introduces a cut among heterozygous (677 CT) and three bands of 198 bp, 175 bp and 23 bp. The homozygous (677 TT) had two bands of 175 bp and 23 bp. The size of the amplified product was read with the use of a DNA ladder of different molecular weights (fermentas, No Limits™ 100 bp DNA Fragment, catalogue number SM1441).
MTHFR 1298 A→C polymorphism
The 1298 A→C mutation was analyzed by the method described by Radha Rama Devi et al.  PCR amplification of exon 7 of the MTHFR gene using 5′ CTT TGG GGA GCT GAA GGA CTA CTA C 3′ as the forward primer and 5′ CAC TTT GTG ACC ATT CCG GTT TG 3′ as the reverse primer resulted in a 163 bp product. The PCR product was digested with the Mbo II restriction enzyme. The 1298 A/C mutation abolishes one restriction site of Mbo II, resulting in the merger of the 56 and 28 bp bands into an 84 bp band. The PCR conditions were similar to the MTHFR 677C→T polymorphism. Restriction digestion with Mbo II (Fermentas, INC, USA) was carried out on 2 μl buffer, 1 μl of Mbo II, and 8 μl of PCR amplicon, and incubated at 37°C for 10 to 12 hours. The Mbo II digested fragments were separated on 2.5% agarose gel electrophoresis stained with ethidium bromide. The electrophoretic pattern was visualized under UV light and then photographed using a Polaroid camera with a red orange filter. Wild type (1298 AA) produced fragments of 56, 30/31, 28 and 18 bp. Heterozygous (1298 AC) produced fragments of 84, 56, 30/31, 28 and 18 bp, whereas, homozygous for the 1298 polymorphism (1298 CC) produced 84, 30/31 and 18 bp.
Data were summarized and presented in the form of mean, range, percentage and standard deviation as descriptive statistics. Descriptive statistics and statistical comparison were performed using the statistical software program Statistical Package for the Social Sciences (version 16). Regarding the clinical data, comparison was done using the Chi-Square test (x 2 ), whereas for the laboratory data; Independent t-test and analysis of variance test were used. Odds ratio to access the risk conferred by a particular allele or genotype.
A P value < 0.05 was considered to be statistically significant, and also haplotype frequencies were tested.
| > Results|| |
The current study was carried out on 50 patients diagnosed as having DLBCL as well as 50 age matched apparently healthy volunteers (as a control group). Patients included in the study were 23 females (46%) and 27 males (54%). Their age ranged between 22 and 73 years with a mean value of 47.2 ± 13.9 yeas. Control group included 31 females (62%) and 19 males (38%) and the age ranged between 18 and 77 years with a mean value of 45.6 ± 15.3 years. There were no statistically significant differences between the 2 groups with regards to the sex (P value = 0.160) or age (P value = 0.585). Clinical characteristics of patients are summarized in [Table 1].
Performance status values ranged between 0 and 3 with a mean of 1.46 ± 0.78. We studied laboratory data of both the patients and controls and it is presented in [Table 2]. There were highly statistically significant differences between them with regards to the total leucocytic count and hemoglobin level (P value < 0.0001), but there were no statistically significant differences regarding the platelet count (P value = 0.452), performed liver functions (P value = 0.0929) or kidney functions results (P value = 0. 174). Some additional laboratory tests and procedures were performed for the patients to diagnose diffuse large B cell lymphoma (DLBCL), assess staging and prognostic state.
In the patient group, the serum LDH levels ranged between 210 and 564 mg/dl ,with a mean of 308.1 ± 75.4; serum β 2 microglobulin ranged between 2 and 6 mg/L, with a mean of 3.54 ± 1.11; serum albumin levels ranged between 2.5 and 3.9 mg/dl with a mean of 3.38 ± 0.38;lymph node biopsy revealed large cell NHL of the B cell type in 50 patients (100%); and, bone marrow biopsy was involved in 4 patients (8%), and was free in 46 patients (92%). With regards to the flow cytometry results, CD20 was positive in 50 patients (100%), CD3 was negative in 50 patients (100%) and CD5 was positive in 29 patients (58%) and was negative in 21 patients (42%). Cerebrospinal fluid (CSF) analysis was free in 50 patients (100%), X rays and CT were free in 15 patients (30%) and were involved in 35 patients (70%).
Concerning the results of PCR-RFLP for MTHFR 677C→T polymorphism in the patient group, 32 patients (64%) were homozygous for wild allele (CC), 10 patients (20%) were heterozygous for mutant allele (CT) and 8 patients (16%) were homozygous for mutant allele (TT). For the control group, 46 cases (92%) had CC genotype, 3 cases (6%) had CT genotype while 1 cases (2%) had TT genotype. Relations between patients and controls regarding C allele (CC/CT) and T allele (CT/TT) frequencies were also done [summarized in [Table 3]]. There were statistically significant differences between the patient and control groups as regard the results of PCR-RFLP for MTHFR 677C→T polymorphism for CC (P value = 0.001), CT (P value = 0.048) and TT (P value = 0.038) genotypes, but no statistically significant differences regarding CC/CT or TT/CT alleles (P value = 0.0527).
|Table 3: Summary of the genotype and allele frequencies in patients and control groups for MTHFR 677C#8594;T and MTHFR 1298 A#8594;C polymorphisms in the study|
Click here to view
Concerning the results of PCR-RFLP for MTHFR 1298 A→C polymorphism in the patient group, 15 patients (30%) were homozygous for wild allele (AA), 25 patients (50%) were heterozygous for mutant allele (AC) and 10 patients (20%) were homozygous for mutant allele (CC). For the control group, 45cases (90%) had AA genotype, 4cases (8%) had AC genotype while 1 cases (2%) had CC genotype. Relations between patients and controls regarding A allele (AA/AC) and C allele (CC/AC) frequencies were also done [summarized in [Table 3]]. There were highly statistically significant differences between the patient and control groups for the AA, AC genotypes as well as the AA/AC and CC/AC alleles (P value < 0.0001), statistically significant difference regarding CC genotype (P value 0.0192). We did not found any statistically significant differences between patient and control groups with any of the haplotype frequencies shown in [Table 4].
|Table 4: Summary of the haplotype frequencies for MTHFR 677C#8594;T and MTHFR 1298 A#8594;C polymorphisms in patients and control groups in the study|
Click here to view
| > Discussion|| |
Folate and methionine metabolism play an essential role in both, the DNA synthesis as well as methylation. Polymorphisms in the genes of the folate-dependent enzymes have been shown to affect the disease susceptibility. To evaluate whether genetic variation in folate metabolism may have a role in the risk of non-Hodgkin's lymphoma, we studied MTHFR677 C/T, MTHFR1298 A/C polymorphisms in 50 patients diagnosed as having DLBCL as well as in 50 age matched apparently healthy adults enrolled as the control group. We found evidence for an association between MTHFR677 C/T polymorphisms and DLBCL. MTHFR 677CT, TT genotypes were associated with an increased risk for DLBCL(OR>1). Furthermore, we observed highly increased risks for DLBCL associated with MTHFR1298 AC, CC genotypes (OR>1) and with C allele.
The reduced enzyme activities of the MTHFR 677TT and MTHFR 1298CC genotypes lead to increased 5,10-methylene THF availability for DNA synthesis,  which may protect cells from DNA damage. Consistent with this hypothesis, several studies have shown that the MTHFR 677TT genotype has been associated with reduced risk of malignant lymphoma,  and ALL. , Conversely, the MTHFR 677TT genotype has also been associated with an increased risk for NHL and follicular lymphoma (FL).  Skibola et al.,  suggested that the increased risk associated with NHL may be attributed to the reduction in the 5, 10-methylene THF availability due to low folate and elevated homocysteine levels. However, two recent reports showed no association between MTHFR 677TT and FL in France  and NHL in England.  Kim et al.,  reported that both the MTHFR 677CT and 677TT genotypes showed decreased risk for NHL, including DLBCL, but did not affect the risk for T-cell lymphoma. The MTHFR 1298CC genotype showed a significantly increased risk for NHL and T-cell lymphoma, whereas the MTHFR 1298AC genotype was not associated with NHL and any subtype. These results suggest that the 677T allele decreases the risk for NHL and that the 1298C allele may be inversely associated with NHL.
Studies have suggested that the cancer risk associated with the MTHFR polymorphisms may exhibit a gene-nutrient interaction that depends on the level of folate intake. , Based on this hypothesis, when folate intake is sufficient, individuals with the variant MTHFR genotypes may have a reduced risk, because under these conditions, adequate provision of methyl donors could still be ensured, which would enhance DNA synthesis affected by inhibition of the 5-methyl-tetrahydrofolate pathway due to diminished MTHFR enzyme activity, and thus, result in a decreased risk of DNA damage. However, in the presence of low folate intake, both impaired DNA methylation and DNA synthesis/repair may become the primary mechanism of carcinogenesis in those who have the variant MTHFR genotypes. In agreement with this hypothesis, several case-control studies have shown that in those with the variant MTHFR 677T allele, decreased risk of colorectal neoplasia was observed among subjects with adequate folate levels, and elevated risk was observed among subjects with low folate intake. 
The interaction between MTHFR polymorphisms and the folate status has been documented in several studies. This interaction attracts even more attention because a protective association between folate supplements in pregnancy and the risk of childhood ALL has been demonstrated.  One of the molecular mechanisms through which the MTHFR polymorphisms increase the risk of developing malignancy may be DNA hypomethylation. Growth inducing genes such as oncogenes, in contrast, may be overexpressed when they are hypomethylated.  In a recent study, it was shown that genomic DNA methylation was significantly lower in the subjects with the MTHFR 677TT genotype compared with those with the 677CC genotype, and the methylation status in subjects with the MTHFR 677TT genotype was directly correlated with red blood corpuscles' (RBC) folate levels.  Taken together, these data provide very plausible molecular mechanisms through which suboptimal cellular folate levels and the MTHFR polymorphisms could increase the risk for development of malignancy.
The study carried out among the Indian and Filipino pediatric population reported a significant increase in the risk of ALL. Reddy et al.,  observed a two-fold increased risk in developing ALL for the 677 homozygous and heterozygous genotype, and a 1.9 fold increased risk for the 1298 homozygous and heterozygous polymorphisms. A combined heterozygous genotype for both polymorphisms (677 C→T and 1298 A→C) would increase the risk five folds.  The Filipino study also observed an increase in risk of 1.57 fold for one polymorphism, and a 2.69 fold increase in risk when both polymorphisms were considered together.  We studied MTHFR677 C/T, MTHFR1298 A/C haplotypes and we observed three haplotypes (HapA, HapB, and HapC) accounted for the majority of estimated haplotypes with no association between NHL and different haplotypes. Our results were supported by Lightfoot et al.,  who reported no significant associations between studied haplotypes and NHL. Kim et al.,  also studied the distribution of haplotype frequencies of MTHFR between the cases and controls and found that Hap C (677T-1298A) was associated with decreased risk for NHL and DLBCL, but not for T-cell lymphoma. Hap B (677C-1298C) was associated with increased risk for only T-cell lymphoma.
In conclusion, this study demonstrates a significant association between the MTHFR polymorphisms and the risk of DLBCL, providing a genetic basis for the hypothesis that low folate intake and/or impaired folate metabolism may play a role in lymphomagenesis. However, the data reported here has several limitations. One, our sample consisted of a small number of subjects. In addition, we did not determine the serum folate levels or the dietary intake. Therefore, further studies, consisting of a larger number of subjects are necessary. Additional studies on the role of gene (the MTHFR polymorphisms) environment (folate intake) interaction are needed to confirm the role of these genetic polymorphisms in the susceptibility to lymphoma.
| > Acknowledgements|| |
We would like to express our gratitude to the nursing team of the Hematology Unit, Nuclear Medicine and Oncology Department in Faculty of medicine, Cairo University, for helping us in collecting the samples from patients after obtaining their written informed consent.
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[Table 1], [Table 2], [Table 3], [Table 4]
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