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Background:
Systematic Review

MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis

by
Savvas Kolanis
1,
Eleni P. Kotanidou
1,
Vasiliki Rengina Tsinopoulou
1,
Elisavet Georgiou
2,
Emmanuel Hatzipantelis
1,
Liana Fidani
1,3 and
Assimina Galli-Tsinopoulou
1,*
1
2nd Department of Paediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636 Thessaloniki, Greece
2
Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
3
Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
Children 2025, 12(1), 108; https://doi.org/10.3390/children12010108
Submission received: 12 December 2024 / Revised: 5 January 2025 / Accepted: 13 January 2025 / Published: 17 January 2025
(This article belongs to the Special Issue Children with Cancer Diseases: The Present and a Challenge for Future)
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Abstract

:
Background/Objectives: MTHFR gene polymorphisms (677C>T and 1298A>C) correlate with various types of cancer across all age groups; however, a small number of studies have included solely children and adolescents. The aim of this systematic review and meta-analysis was to present and synthesize all the available evidence on the association between MTHFR gene polymorphisms and the incidence of all types of cancer in children and adolescences. Methods: After a systematic search of all of the available data, original case–control studies involving children or adolescents with a confirmed diagnosis of any type of cancer and a molecular genetic test of MTHFR gene polymorphisms were included. Results: A total of 53 original studies in children and adolescents with cancer were included in the systematic review. Among these, 40 studies reviewed children and adolescents with Acute Lymphoblastic Leukemia (ALL), 4 those with Acute Myeloblastic Leukemia (AML), 8 those with central nervous system (CNS) tumors and 3 those with other types of cancer. Children and adolescents with ALL had less frequent T allele sequences (CT and TT variations) of the 677C>T polymorphism compared to a healthy population (OR: 0.85; CI: 0.80–0.91; p < 0.00001). Concerning the 1298A>C polymorphism, the C allele sequences (AC and CC) did not present a statistically significant difference in frequency compared to a healthy population (OR: 1.01; CI: 0.95–1.08; p = 0.69). Conclusions: Children and adolescents with ALL appeared to have the T allele sequences of the 677C>T polymorphism of the MTHFR gene less frequently compared to a healthy population.

1. Introduction

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, located on the short arm of chromosome 1, produces a 656-amino-acid protein of paramount importance in folate metabolism and therefore in deoxyribonucleic acid (DNA) methylation [1,2,3]. This enzyme catalyzes the reductive reaction of 5,10-MethylTHF into 5-MethylTHF, which is the only source of 5-MethylTHF (the biologically active form of folate) in cells and is additionally used as a co-substrate for the remethylation of homocysteine into methionine. The 5-10 MTHFR enzyme therefore plays a central role in the metabolism of homocysteine (Hcy) and of folic acid, which is even more evident, as mutations and polymorphisms of the MTHFR gene lead to hyperhomocysteinemia and reduced levels of 5-MethylTHF [4,5].
Hundreds of MTHFR gene polymorphisms have been discovered in recent decades. The ClinVar archive by the National Institute of Health reports 945 variations in the MTHFR gene, 93 of which are registered as pathogenic [6]. The three most common polymorphisms are located at nucleotide positions 677, 1298 and 1317. The single-nucleotide polymorphism (SNP) 677C>T results in a heat-sensitive variant of the final protein product with reduced enzyme activity. This SNP is located in exon 4 of the MTHFR gene, where cytosine is replaced by thymine, causing a change in the nature of the enzyme, as it results in the substitution of the amino acid valine for alanine. The SNP 1298A>C occurs in exon 7 within the region of the considered regulatory domain, as adenine is replaced by cytosine, also resulting in a change in the protein produced, with the conversion of glutamic acid into alanine. Finally, the third SNP 1317T>C is located in the same region, in exon 7, causing a silent mutation without a change in the function of the final product and without clinical significance [3,7,8].
The 677C>T polymorphism (rs1801133) of the MTHFR gene is one of the most common polymorphisms of the MTHFR gene, and many researchers have suggested that it leads to hyperhomocysteinemia. The 1000 Genomes Project reported that this particular polymorphism is recognized worldwide in approximately 25% of people, with the highest frequency in Hispanic and European populations (47% and 36%, respectively), followed by Asian populations (East Asia at 30% and South Asia at 12%) and with the lowest frequency in African populations (9%) [9,10,11]. This particular polymorphism is associated with compromised reductase activity, with this enzyme’s function and activity reported to be reduced by up to 50%, resulting in an increase in Hcy levels of approximately 30% [3,12]. This observation is mainly reported in individuals homozygous for this particular SNP (TT variant), with the lowest recorded enzyme activity and consequently the highest Hcy levels and reduced plasma folate levels [3,4]. Moreover, researchers suggest that supplementation with the active form of folate (5-MethylTHF) provides a protective effect in patients carrying this particular SNP, as their folate levels are normalized and the risk of diseases associated with hyperhomocysteinemia is minimized [13,14,15,16,17,18].
The 1298A>C (rs1801131) polymorphism does not appear to affect Hcy or folate levels. However, double heterozygosity for the 677C>T and 1298A>C alleles in individuals could be responsible for reduced plasma folate and an increased Hcy concentration and is also strongly implicated in renal failure and several other diseases [12,19].
MTHFR gene polymorphisms are associated with an increased incidence of various cancer and malignancies across all ages but are also associated with non-communicable diseases. The 677C>T polymorphism is associated with colon, breast, pancreas and stomach cancer and also with heart disease, hypertension, diabetes mellitus type 1 and type 2, hypothyroidism and other conditions such as autism spectrum disorder, birth defects, congenital heart disease, neonatal defects and Down’s syndrome. The 1298A>C polymorphism is associated with myocardial infarction, stroke, diabetic nephropathy, autism spectrum disorders and recurrent pregnancy loss [7,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. The evidence regarding the association between Acute Lymphoblastic Leukemia (ALL) and MTHFR polymorphisms across all ages is inconsistent [42,43,44]. In addition, hyperhomocysteinemia, a condition often resulting from MTHFR gene polymorphisms, is an independent risk factor for several types of cancer [45]. Many studies have investigated MTHFR polymorphisms in relation to the incidence of the most common types of cancer across one’s lifespan. Childhood and adolescent cancers have distinct etiologies, genetic backgrounds, epidemiological distributions and microenvironmental characteristics compared to those of adult cancers [46,47].
The current systematic review and meta-analysis aimed to present and synthesize the available evidence on the relation between MTHFR polymorphisms and cancer incidence in children and adolescences.

2. Materials and Methods

The eligibility criteria included original case–control studies consisting of children or adolescents (up to 21 years of age). A confirmed diagnosis of any type of cancer was required in the patient group, and a molecular genetic test of MTHFR gene polymorphisms (confirmed using genetic testing, a Sanger analysis, direct sequencing or any other molecular method) was also required for all participants. The study protocol was registered in the International Prospective Register of Systematic Reviews (Prospero, Registration number: CRD42024564716). There was no restriction on the publication status of the candidate studies during the study selection. Only studies published in the English language were included.
Studies and registries were identified from the MEDLINE, Scopus, ScienceDirect, EBSCO, Cochrane Library and ClinicalTrials.gov databases. The database search was also restricted to studies published between March 1998 and July 2024. The search strategy in MEDLINE (PubMed) was (MTHFR or methylenetetrahydrofolate reductase) and (cancer or neoplasms) and (children or adolescents). The search strategy for ScienceDirect was (MTHFR gene OR MTHFR) AND (cancer OR malignancy) AND (children or adolescents). The search strategy for EBSCO was (“MTHFR” OR “methylenetetrahydrofolate reductase” OR “MTHFR gene polymorphisms” OR “677” OR “1298”) AND (“cancer” OR “malignancies” OR “neoplasms” OR “ALL”) AND (“children” OR “adolescent”). The search strategy for Cochrane Library was MTHFR gene or Methylenetetrahydrofolate Reductase. The search strategy for ClinicalTrials.gov was the use of MTHFR OR MTHFR gene mutations as the search filters.
A review management tool was used to assess eligible studies, and a prototype data extraction form was also created to categorize all of the extracted data. The selection process and the data extraction process were performed by two independent investigators (with screening and inclusion based on the eligibility criteria). All disagreements were resolved by a third party. The team of researchers was gathered prior to the study selection and data extraction phases and conducted pilot testing in an effort to minimize errors. No automation tools were used. The data extracted from the selected studies consisted of the following: study ID, published title, authors, date of publication and country of origin, population’s origin, type of cancer/malignancy, staging, genetic variance method, study’s funding. Sample size, gender (male/female), age (mean value and range), MTHFR gene polymorphism 677C>T variants (CC, CT, TT) and MTHFR gene polymorphism 1298A>C variants (AA, AC, CC) were recorded separately for the patient and control groups. When data were missing from a study, we used simple statistical methods (mean values, conversion of percentages and addition/subtraction) to obtain them, or we attempted to contact the authors to obtain the relevant missing data. This study’s design, protocol and methods were based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [48] (Table S1 in Supplementary Materials).
A qualitative assessment of the case–control studies included was performed based on the Newcastle–Ottawa scale (NOS) star rating system, as recommended by the Cochrane Handbook for Systematic Reviews and Meta-analyses [49,50]. The evaluation assessed the 3 key perspectives in each study design: the selection of the participants in each group, the comparability of the groups and the ascertainment of exposure.
The primary outcome of this study was to report the incidence of MTHFR polymorphisms amongst children and adolescents with any type of diagnosed cancer or malignancy. The outcomes were sorted and presented separately per category. A subgroup analysis was performed based on the country and continent of the researched population. The risk of publication bias was managed using a funnel plot analysis.

Data Synthesis and Statistical Analysis

Homogenous data were synthesized using the Comprehensive Meta-Analysis software and Review Manager software, RevMan v.5.4 by Cochrane Collaboration. A meta-analysis was conducted among studies in children and adolescents with ALL, as we assessed that the eligible studies were sufficiently homogeneous in design and comparison. In the other cancer categories, no further statistical synthesis was performed due to heterogeneity and/or due to an insufficient number of studies.
Dichotomous data were determined using odds ratios (Ors) with 95% confidence intervals (Cis). Continuous outcomes were analyzed using weighted mean differences (with the 95% CI) or standardized mean differences (95% CI) when different measurement scales were used. The Chi-square test and the I2 test were used to define heterogeneity. Statistical heterogeneity was tested using the Chi-square test (significance level: 0.1) and the I2 statistic. For high levels of heterogeneity (I2 ≥ 50% or p < 0.1), the study design and characteristics were evaluated in the included studies as suggested by the Cochrane Handbook for Systematic Reviews. We performed a subgroup analysis based on the populations’ origins. In order to control for publication bias (meta-bias), a funnel plot was applied, and Egger’s regression test (publication bias if p < 0.05) was performed [51].

3. Results

3.1. Acute Lymphoblastic Leukemia (ALL)

A total of 1597 studies were reviewed through databases and registries. After removing duplicate studies, the remaining records were assessed for eligibility according to the inclusion and exclusion criteria, as shown in the flow chart (Figure 1). The search concluded with a total of 50 articles being reviewed at full-text level. A total of 13 articles were excluded for different reasons [52,53,54,55,56,57,58,59,60,61,62,63,64]. The final qualitative and quantitative synthesis included 40 original studies with a total of population of 7704 ALL patients and 10,825 control participants [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104] (Table S2 in Supplementary Materials).
Male participants were more numerous than females in both the patient and control groups in the included studies (56.83% vs. 43.17% in patient groups and 53.11% vs. 46.89% in control groups).
The statistical synthesis recorded the incidence of the MTHFR polymorphisms (677C>T and 1298A>C) amongst children and adolescents with the diagnosis of ALL. Children and adolescents with ALL presented with the T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene less frequently when compared with a healthy population (OR: 0.85; CI: 0.80–0.91; p < 0.00001) (Figure 2).
Additionally, children and adolescents with ALL and the C allele sequences (AC and CC) of the 1298A>C polymorphism of the MTHFR gene did not present a statistically significant difference in their frequency compared to that in a healthy population (OR: 1.01; CI: 0.95–1.08; p = 0.69) (Figure 3).
A subgroup analysis of the 677C>T polymorphism showed results consistent with the analysis of the entire group. Children and adolescents with ALL originating from South American countries had T allele sequences (CT and TT) of the 677C>T polymorphism of the MTHFR gene less frequently compared with a healthy population of the same origin (OR: 0.68; CI: 0.53–0.87; p = 0.002). Similar results were also observed in children and adolescents originating from Asia and Europe (OR: 0.78; CI: 0.71–0.86; and p < 0.00001 and OR: 0.89; CI: 0.81–0.98; and p = 0.02, respectively) (Figure 4).
A subgroup analysis of the 1298A>C polymorphism of the MTHFR gene did not show a significant difference in the frequency of C allele sequences (AC and CC) in children and adolescents of Asian or European origin compared with a healthy population of the same origin (OR: 0.96; CI: 0.87–1.06; and p = 0.38 and OR: 1.03; CI: 0.93–1.14; and p = 0.34, respectively). However, children and adolescents with ALL originating from South American countries had the C allele sequences (AC and CC) more frequently compared with a healthy population of the same origin (OR: 1.48; CI: 1.15–1.89; p = 0.002) (Figure 5).
The analysis of publication bias for both polymorphisms (677C>T and 1298A>C) showed no significant bias, with symmetric diagrams in the funnel plot analysis, which was further verified using Egger’s regression test (p > 0.05) (Figure 6).

3.2. Acute Myeloblastic Leukemia (AML)

Four studies involving children and adolescents with AML were eligible and included in the present review, synthesizing data from a total of 339 children and adolescents in the patient groups and 1414 participants in the control groups. Children and adolescents with AML, when compared with a healthy population, did not present a difference in the studied prevalence of MTHFR polymorphisms (677C>T and 1298A>C). The only exception was the case–control study by Lightfoot et al. [86], in which 89 children and adolescents were included in the patient group, concluding that children and adolescents with AML had the CT variant of the 677C>T polymorphism less frequently compared with the control group (Table 1).

3.3. Central Nervous System (CNS) Tumors

We identified eight studies that included children and adolescents with eligible central nervous system (CNS) tumors. Three studies on various types of CNS tumors [107,108,109], which included a total of 678 children and adolescents in the patient groups, showed that there was no statistically significant difference in the frequency of MTHFR polymorphisms (677C>T and 1298A>C) compared with that in a healthy population. The study by De Miranda et al. [110], which included 29 children and adolescents with neuroblastomas in the patient group, did not show a statistically significant difference in the frequency of the 677C>T polymorphism compared with that in 92 healthy participants. Finally, we included four other eligible studies using our protocol that included 326 children and adolescents with retinoblastomas and 490 participants in the control groups [111,112,113,114]. The study by Soleimani et al. [112] reported that 96 children and adolescents with retinoblastomas had the 677C>T polymorphism less frequently, as both heterozygous and homozygous variants were recorded less frequently (OR: 0.51 and p = 0.031 and OR: 0.23 and p = 0.025, respectively). On the contrary, the study by Bisht et al. [113] reported that the SNPs 677C>T and also 1298A>C were associated with an increased incidence of retinoblastoma in children and adolescents, as CT variants were reported at a lower frequency in the control group (ORs: 16.02 and 10.2, respectively; p < 0.0001). The other two eligible studies [111,114] did not show a statistically significant association between MTHFR polymorphisms (677C>T and 1298A>C) and the incidence of retinoblastoma (Table 2).

3.4. Other Types of Cancer

Three eligible studies were identified that included children and adolescents with other types of cancer. The study by Stanulla et al. [115], which included 487 children and adolescents in the patient group with non-Hodgkin lymphoma, showed that the 677C>T polymorphism of the MTHFR gene did not appear at a different frequency compared to that in the healthy population. The study by Patîno-Garcia et al. [116], which included 96 children and adolescents with osteosarcomas, showed that the MTHFR polymorphisms (677C>T and 1298A>C) did not have a statistically significant difference in frequency compared to that in the healthy population. Finally, the study by Ferrara et al. [117], which included 34 children and adolescents with Wilms’ tumors, showed that the TT variant of the 677C>T polymorphisms occurs more frequently compared to its frequency in the healthy population (Table 3).

3.5. Quality Assessment of the Included Studies

This study conducted a quality assessment of 53 original case–control studies included in the systematic review and the meta-analysis. The studies included were assessed as high-quality, as they scored 7 or higher on the star-based system according to the Newcastle–Ottawa scale (NOS) (Table S3 in Supplementary Materials).

4. Discussion

The primary outcome of the present systematic review and meta-analysis was to present the incidence of MTHFR polymorphisms among children and adolescents with any type of cancer. The vast majority of eligible studies included children and adolescents with ALL. A total of 40 studies in our analysis included data from 7704 children and adolescents in the patient groups and 10,825 in the control groups. Children and adolescents with ALL appeared to have T allele sequences (CT and TT variants) of the 677C>T polymorphism of the MTHFR gene less frequently when compared with the healthy population. The suggested protective effect of the 677C>T polymorphism in children and adolescents with ALL contradicts the known association between this polymorphism, hyperhomocysteinemia and cancer. However, this protective effect has also been reported in the association of MTHFR polymorphisms with gliomas and MTHFR polymorphisms with hypothyroidism [21,30]. No difference in the 1298A>C polymorphism of the MTHFR gene was investigated in children and adolescents with ALL compared with that in the healthy controls. The subgroup analysis, based on country and continent of origin, revealed that the T allele sequences (CT and TT variants) of the 677C>T polymorphism of the MTHFR gene were recorded less frequently in children and adolescents from the South American, Asian and European subgroups compared to healthy populations of the same origin.
The subgroup analysis of the 1298A>C polymorphism of the MTHFR gene showed that children and adolescents from South America had the C allele sequences (AC and CC variants) more frequently compared with a healthy population of the same origin. The results of the different studies occasionally contradicted each other, for which there are various possible explanations. This includes the influence of the type of population studied because of the difference between the results from the Asian and European studies. Based on numerous studies, it is acceptable to hypothesize that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with variations in the susceptibility rates for 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 [118]. Generally, it is clear that susceptibility to childhood ALL is partly related to constitutional differences in folate gene polymorphisms. Among the four studies included on children and adolescents with AML, in the present systematic review, there was no difference in the frequency of either MTHFR gene polymorphisms (677C>T and 1298A>C) between the patients and controls, except for one case–control study [86], where the CT variant of the 677C>T polymorphism was less frequently reported in the patient group when compared with the control group. The eight studies included involving children and adolescents with CNS tumors in the present systematic review revealed contradictory findings. Among children and adolescents with retinoblastoma, both variants of the 677C>T polymorphism (CT and TT) were reported less frequently compared to their frequency in a healthy population [112], whereas the CT variant of 677C>T and the AC variant of the 1298A>C polymorphism appeared 10 times more frequently (even 16 times more for the CT variation of 677C>T) compared with their frequency in a healthy population in another protocol [113]. Finally, children and adolescents with Wilms’ tumors presented with the TT variant of the 677C>T polymorphisms more frequently compared to its frequency in a healthy population [117].
The present study represents a systematic review of all of the available literature, focusing on the association of MTHFR gene polymorphisms and cancer in children and adolescents in a comprehensive manner. Previously published systematic reviews and meta-analyses including children and adolescents with ALL have shown significant inconsistency in investigating the possible associations between ALL and MTHFR gene polymorphisms [42,43,118,119,120,121,122,123]. Many investigators have suggested that there is no association between the 677C>T polymorphism of the MTHFR gene and children and adolescents with ALL [42,44,120,121]. Others have suggested that there is a slightly increased incidence of the 677C>T polymorphism in children and adolescents with ALL, while others have suggested that its incidence is reduced [29,43,118,119,123]. Similar inconsistency has been observed in the findings of studies on the 1298A>C polymorphism [42,43,118,119,120,121,122]. The discrepancies between our study and similar studies on the same questions probably arise due to their inclusion of case–control studies with a mixed-age population, in contrast to the present study, in which the age of the population was specific. Our analysis is consistent with the meta-analysis performed 12 years earlier by Yan et al. [119] in 2012, which also included studies exclusively on children and adolescents and obtained similar results to the findings of this study. However, our findings include the incorporation of new data from more original case studies. Additionally, the hereby conducted subgroup analysis provides further insights into the association of MTHFR gene polymorphisms based on the population’s origin, with interesting findings regarding the geographical variation in the investigated differences in polymorphisms in children and adolescents with ALL.
A recent systematic review and meta-analysis by Gohari et al. examined the correlation between MTHFR gene polymorphisms (677C>T and 1298A>C) in children and adolescents and retinoblastoma when compared with healthy controls [124]. Its findings supported that the 677C>T polymorphism is associated with susceptibility to retinoblastoma. However, the current study did not perform a statistical analysis due to the small number of the studies that met the eligibility criteria and due to their high heterogeneity.
A systematic review and meta-analysis by Qin et al. investigated the association between the MTHFR gene polymorphisms (677C>T and 1298A>C) and patients with AML compared to their frequency in a healthy population [125]. The authors concluded that there was no association between the two groups; however, they included several studies that consisted of adults or mixed-age populations, and thus, their conclusions apply to all age groups and may differ from those for pediatric AML. A different systematic review and meta-analysis by Wang et al. examined the association of the MTHFR gene polymorphisms (677C>T and 1298A>C) and patients with non-Hodgkin lymphoma compared to a healthy population [126]. They also similarly included many adult studies with mixed populations, and therefore, their conclusions may not apply to the pediatric population.
Based on the synthesis performed of the previously mentioned evidence, it is well established that a correlation between MTHFR gene polymorphisms (677C>T and 1298A>C) and ALL among children and adolescents emerges, which is of high interest. For other types of cancer, more studies that include solely children and adolescents are needed in order to extract firm and valid conclusions.
MTHFR gene polymorphisms have attracted even greater attention in the medical community in recent years due to their association with methotrexate. Methotrexate is a widely used drug in a variety of cancer treatments. It inhibits the action of dihydrofolate reductase within the folate cycle, thereby reducing tetrahydrofolate levels [127]. MTHFR gene polymorphisms result in reduced levels of the active form of folic acid (5-MethylTHF). Research has examined the potential implication of MTHFR gene polymorphisms in the adverse events and toxicity of methotrexate as part of cancer treatment, providing a new perspective on the clinical implications of the MTHFR gene. Specifically, it has been reported that children and adolescents with ALL and a confirmed 677C>T polymorphism of the MTHFR gene are more prone to mucositis and gastrointestinal-related adverse events, liver damage and lower platelet counts after receiving high doses of methotrexate as part of cancer treatment protocols (in ALL and non-Hodgkin lymphoma) [128,129,130,131,132,133,134,135]. These findings reveal the MTHFR gene as a promising clinical tool when implementing cancer treatment protocols. The identification of MTHFR gene polymorphisms in children and adolescents provides a prognosis and early prediction of the aforementioned adverse events and is therefore related to overall morbidity.
The present analysis included studies that consisted exclusively of children and adolescents and did not include studies with mixed elderly populations, therefore strengthening the resulting findings. Additionally, this review presented the association of MTHFR gene polymorphisms by cancer type, providing a comprehensive overview across distinct oncological entities with different clinical and molecular backgrounds. The statistical analysis in the current study only compared wild-type sequences with mutant sequences in studies that included children and adolescents with ALL (CC vs. CT and TT for the 677C>T polymorphism and AA vs. AC and CC for the 1298A>C polymorphism). We only included studies published in the English language. Statistical analyses were not performed for any other cancer types due to the limited studies per category and due to the heterogeneity of the studies included.

5. Conclusions

The present analysis suggests an association between the 677C>T polymorphism of the MTHFR gene and a diagnosis of ALL among children and adolescents. Pediatric and adolescent ALL patients appear to have T allele sequences (CT and TT variants) less frequently compared to the healthy population. These findings were confirmed in our subgroup analysis of populations from Europe, Asia and South America. The 1298A>C polymorphism of the MTHFR gene does not show any difference between children and adolescents with ALL and healthy controls. However, in the subgroup analysis, children and adolescents with ALL that originated from South American countries have C allele sequences (AC and CC variations) of the 1298A>C polymorphism more frequently compared to the same healthy population. Children and adolescents with AML or CNS tumors do not show significant differences in the distribution of MTHFR polymorphisms compared with that in healthy controls. For children and adolescents with retinoblastoma, inconsistent and contradictory findings are encountered regarding the role of MTHFR gene polymorphisms. There are insufficient data to extract valid conclusions regarding the relationship between MTHFR gene polymorphisms and other types of cancer in childhood and adolescence.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/children12010108/s1. Table S1: PRISMA 2020 Checklist of the systematic review; Table S2: Baseline Characteristics of studies included in the systematic review; Table S3: Newcastle-Ottawa scale of studies included in the systematic review.

Author Contributions

Conceptualization: S.K. and A.G.-T. Methodology: S.K. and E.P.K. Software: S.K. Validation: S.K., E.G., L.F., E.H. and E.P.K. Formal analysis: S.K. Investigation: S.K. and E.P.K. Data curation: S.K. Writing—original draft preparation: S.K., E.P.K., V.R.T., E.G., L.F., E.H. and A.G.-T. Writing—review and editing: A.G.-T. Visualization: S.K. Supervision: A.G.-T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

There were no ethical conflicts since the analysis included only original studies that had already requested permission for genetic analysis and had been already approved by ethics committees.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Planello, A.C.; Villela, D.; Loureiro, T. MTHFR Genetic Testing: Is There a Clinical Utility? Rev. Assoc. Med. Bras. 2024, 70, e20240215. [Google Scholar] [CrossRef] [PubMed]
  2. Weile, J.; Kishore, N.; Sun, S.; Maaieh, R.; Verby, M.; Li, R.; Fotiadou, I.; Kitaygorodsky, J.; Wu, Y.; Holenstein, A.; et al. Shifting Landscapes of Human MTHFR Missense-Variant Effects. Am. J. Hum. Genet. 2021, 108, 1283–1300. [Google Scholar] [CrossRef] [PubMed]
  3. Raghubeer, S.; Matsha, T.E. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients 2021, 13, 4562. [Google Scholar] [CrossRef]
  4. Zarembska, E.; Ślusarczyk, K.; Wrzosek, M. The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases. Int. J. Mol. Sci. 2023, 25, 193. [Google Scholar] [CrossRef]
  5. Mazokopakis, E.E.; Papadomanolaki, M.G.; Papadakis, J.A. Association of Methylene Tetrahydrofolate Reductase (MTHFR) Gene Polymorphisms with Serum Folate, Cobalanin and Homocysteine Concentrations in Greek Adults. Scand. J. Clin. Lab. Investig. 2023, 83, 69–73. [Google Scholar] [CrossRef]
  6. “MTHFR”[GENE]—ClinVar—NCBI. Available online: https://www.ncbi.nlm.nih.gov/clinvar (accessed on 23 December 2024).
  7. Cai, Y.; Liu, B.; Zhang, Y.; Zhou, Y. MTHFR Gene Polymorphisms in Diabetes Mellitus. Clin. Chim. Acta 2024, 561, 119825. [Google Scholar] [CrossRef]
  8. Botto, L.D.; Yang, Q. 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. Am. J. Epidemiol. 2000, 151, 862–877. [Google Scholar] [CrossRef]
  9. Graydon, J.S.; Claudio, K.; Baker, S.; Kocherla, M.; Ferreira, M.; Roche-Lima, A.; Rodríguez-Maldonado, J.; Duconge, J.; Ruaño, G. Ethnogeographic Prevalence and Implications of the 677C>T and 1298A>C MTHFR Polymorphisms in US Primary Care Populations. Biomark Med. 2019, 13, 649–661. [Google Scholar] [CrossRef]
  10. Liu, T.; Momin, M.; Zhou, H.; Zheng, Q.; Fan, F.; Jia, J.; Liu, M.; Bao, M.; Li, J.; Huo, Y.; et al. Exome-Wide Association Study Identifies East Asian-Specific Missense Variant MTHFR C136T Influencing Homocysteine Levels in Chinese Populations RH: ExWAS of THCY in a Chinese Population. Front. Genet. 2021, 12, 717621. [Google Scholar] [CrossRef]
  11. Byrska-Bishop, M.; Evani, U.S.; Zhao, X.; Basile, A.O.; Abel, H.J.; Regier, A.A.; Corvelo, A.; Clarke, W.E.; Musunuri, R.; Nagulapalli, K.; et al. High-Coverage Whole-Genome Sequencing of the Expanded 1000 Genomes Project Cohort Including 602 Trios. Cell 2022, 185, 3426–3440.e19. [Google Scholar] [CrossRef]
  12. Dean, L. Methylenetetrahydrofolate Reductase Deficiency. 8 March 2012 [Updated 4 November 2024]. In Medical Genetics Summaries; Pratt, V.M., Scott, S.A., Pirmohamed, M., Esquivel, B., Kattman, B.L., Malheiro, A.J., Eds.; National Center for Biotechnology Information (US): Bethesda, MD, USA, 2012. Available online: https://www.ncbi.nlm.nih.gov/books/NBK66131/ (accessed on 23 December 2024).
  13. Ledowsky, C.J.; Schloss, J.; Steel, A. Variations in Folate Prescriptions for Patients with the MTHFR Genetic Polymorphisms: A Case Series Study. Explor. Res. Clin. Social. Pharm. 2023, 10, 100277. [Google Scholar] [CrossRef]
  14. Golja, M.V.; Šmid, A.; Kuželički, N.K.; Trontelj, J.; Geršak, K.; Mlinarič-Raščan, I. Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate. J. Clin. Med. 2020, 9, 2836. [Google Scholar] [CrossRef] [PubMed]
  15. Carboni, L. Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integr. Med. A Clinician’s J. 2022, 21, 36. [Google Scholar]
  16. Hoxha, B.; Hoxha, M.; Zappacosta, B.; Domi, E.; Gervasoni, J.; Persichilli, S.; Malaj, V. Folic Acid and Autism: A Systematic Review of the Current State of Knowledge. Cells 2021, 10, 1976. [Google Scholar] [CrossRef]
  17. Bennett, D.A.; Parish, S.; Millwood, I.Y.; Guo, Y.; Chen, Y.; Turnbull, I.; Yang, L.; Lv, J.; Yu, C.; Davey Smith, G.; et al. MTHFR and Risk of Stroke and Heart Disease in a Low-Folate Population: A Prospective Study of 156 000 Chinese Adults. Int. J. Epidemiol. 2023, 52, 1862–1869. [Google Scholar] [CrossRef] [PubMed]
  18. Khan, K.M.; Jialal, I. Folic Acid Deficiency; StatPearls: Tampa, FL, USA, 2023. [Google Scholar]
  19. Shivkar, R.R.; Gawade, G.C.; Padwal, M.K.; Diwan, A.G.; Mahajan, S.A.; Kadam, C.Y. Association of MTHFR C677T (Rs1801133) and A1298C (Rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease. Indian J. Clin. Biochem. 2021, 37, 224. [Google Scholar] [CrossRef] [PubMed]
  20. Baghad, I.; Erreguibi, D.; Boufettal, R.; Eljai, S.R.; Chihab, F.; Nadifi, S. Association of Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and the Risk of Sporadic Colorectal Cancer. Pan. Afr. Med. J. 2021, 38, 287. [Google Scholar] [CrossRef]
  21. Petrone, I.; Bernardo, P.S.; Dos Santos, E.C.; Abdelhay, E. MTHFR C677T and A1298C Polymorphisms in Breast Cancer, Gliomas and Gastric Cancer: A Review. Genes 2021, 12, 587. [Google Scholar] [CrossRef]
  22. Lal, H.; Sharma, B.; Sambyal, V.; Guleria, K.; Singh, N.R.; Uppal, M.S.; Manjari, M.; Sudan, M. Association of MTHFR 677C>T Polymorphism with Breast Cancer Risk: A Case-Control Study and Meta-Analysis. J. Cancer Res. Ther. 2022, 18, 1451–1460. [Google Scholar] [CrossRef]
  23. Nie, F.; Yu, M.; Zhang, K.; Yang, L.; Zhang, Q.; Liu, S.; Liu, M.; Shang, M.; Zeng, F.; Liu, W. Association of MTHFR Gene Polymorphisms with Pancreatic Cancer: Meta-Analysis of 17 Case-Control Studies. Int. J. Clin. Oncol. 2020, 25, 312–321. [Google Scholar] [CrossRef]
  24. Samii, A.; Aslani, S.; Imani, D.; Razi, B.; Samaneh Tabaee, S.; Jamialahmadi, T.; Sahebkar, A. MTHFR Gene Polymorphisms and Susceptibility to Myocardial Infarction: Evidence from Meta-Analysis and Trial Sequential Analysis. IJC Heart Vasc. 2023, 49, 101293. [Google Scholar] [CrossRef] [PubMed]
  25. Kumar, A.; Sharma, R.; Misra, S.; Nath, M.; Kumar, P. Relationship between Methylenetetrahydrofolate Reductase (MTHFR) Gene (A1298C) Polymorphism with the Risk of Stroke: A Systematic Review and Meta-Analysis. Neurol. Res. 2020, 42, 913–922. [Google Scholar] [CrossRef] [PubMed]
  26. Dong, X.; Wang, J.; Wang, G.; Wang, J.; Wang, L.; Du, Y. MTHFR A1298C Gene Polymorphism on Stroke Risk: An Updated Meta-Analysis. Genes. Environ. 2021, 43, 40. [Google Scholar] [CrossRef]
  27. Liao, S.; Guo, S.; Ma, R.; He, J.; Yan, Y.; Zhang, X.; Wang, X.; Cao, B.; Guo, H. Association between Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and H-Type Hypertension: A Systematic Review and Meta-Analysis. Ann. Hum. Genet. 2022, 86, 278–289. [Google Scholar] [CrossRef]
  28. El Alami, H.; Ouenzar, F.; Errafii, K.; Alidrissi, N.; Belyamani, L.; Ghazal, H.; Wakrim, L.; Abidi, O.; Naamane, A.; Daoud, R.; et al. Meta-Analysis of MTHFR C677T Polymorphism and Type 2 Diabetes Mellitus in MENA Region. Diabetes Metab. Syndr. 2024, 18, 102965. [Google Scholar] [CrossRef]
  29. Huo, Y.; Zhang, W.; Zhang, X.; Su, L.; Li, H.; Wang, F.; Zhang, Y. The Association of Methylenetetrahydrofolate Reductase (MTHFR) A1298C Gene Polymorphism with Susceptibility to Diabetic Nephropathy: A Meta-Analysis. Horm. Metab. Res. 2022, 54, 845–851. [Google Scholar] [CrossRef]
  30. Yang, R.; Pu, D.; Tan, R.; Wu, J. Association of Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms (C677T and A1298C) with Thyroid Dysfunction: A Meta-Analysis and Trial Sequential Analysis. Arch. Endocrinol. Metab. 2022, 66, 551. [Google Scholar] [CrossRef]
  31. Fang, Y.; Cui, Y.; Yin, Z.; Hou, M.; Guo, P.; Wang, H.; Liu, N.; Cai, C.; Wang, M. Comprehensive Systematic Review and Meta-Analysis of the Association between Common Genetic Variants and Autism Spectrum Disorder. Gene 2023, 887, 147723. [Google Scholar] [CrossRef]
  32. Tabatabaei, R.S.; Fatahi-Meibodi, N.; Meibodi, B.; Javaheri, A.; Abbasi, H.; Hadadan, A.; Bahrami, R.; Mirjalili, S.R.; Karimi-Zarchi, M.; Neamatzadeh, H. Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update Meta-Analysis. Fetal Pediatr. Pathol. 2022, 41, 225–241. [Google Scholar] [CrossRef]
  33. Bahrami, R.; Schwartz, D.A.; Asadian, F.; Karimi-Zarchi, M.; Dastgheib, S.A.; Tabatabaie, R.S.; Meibodi, B.; Neamatzadeh, H. Association of MTHFR 677C>T Polymorphism with IUGR and Placental Abruption Risk: A Systematic Review and Meta-Analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2021, 256, 130–139. [Google Scholar] [CrossRef]
  34. Alfaleh, A.; Alkattan, A.; Mahmoud, N.; Alfaleh, F.; Almutair, N.; Alanazi, A.; Kbbash, I.; Radwan, N. The Association Between MTHFR C677T Gene Polymorphism and Repeated Pregnancy Loss in Arabic Countries: A Systematic Review and Meta-Analysis. Reprod. Sci. 2023, 30, 2060–2068. [Google Scholar] [CrossRef] [PubMed]
  35. Mehta, P.; Vishvkarma, R.; Singh, K.; Rajender, S. MTHFR 1298A>C Substitution Is a Strong Candidate for Analysis in Recurrent Pregnancy Loss: Evidence from 14,289 Subjects. Reprod. Sci. 2022, 29, 1039–1053. [Google Scholar] [CrossRef] [PubMed]
  36. Raina, J.K.; Panjaliya, R.K.; Dogra, V.; Sharma, S.; Anupriya; Kumar, P. Association of MTHFR and MS/MTR Gene Polymorphisms with Congenital Heart Defects in North Indian Population (Jammu and Kashmir): A Case-Control Study Encompassing Meta-Analysis and Trial Sequential Analysis. BMC Pediatr. 2022, 22, 223. [Google Scholar] [CrossRef] [PubMed]
  37. Liu, P.F.; Ding, B.; Zhang, J.Y.; Mei, X.F.; Li, F.; Wu, P.; Mei, C.H.; Zhou, Y.F.; Chen, T. Association Between MTHFR C677T Polymorphism and Congenital Heart Disease. Int. Heart J. 2020, 61, 553–561. [Google Scholar] [CrossRef] [PubMed]
  38. Li, J.; Feng, D.; He, S.; Yang, H.; Su, Z.; Ye, H. Association of MTHFR 677C>T Gene Polymorphism with Neonatal Defects: A Meta-Analysis of 81444 Subjects. J. Obs. Gynaecol. 2022, 42, 1811–1822. [Google Scholar] [CrossRef]
  39. Akcılar, R.; Yalınbaş, E.E.; Mutlu, F. MTHFR 677C>T Gene Polymorphism Is Associated with Large for Gestational Age Infants. Fetal Pediatr. Pathol. 2024, 43, 234–245. [Google Scholar] [CrossRef]
  40. Aguilar-Lacasaña, S.; López-Flores, I.; González-Alzaga, B.; Giménez-Asensio, M.J.; Carmona, D.F.; Hernández, A.F.; Gallego, M.F.L.; Romero-Molina, D.; Lacasaña, M. Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth. Nutrients 2021, 13, 831. [Google Scholar] [CrossRef]
  41. Ginani, C.T.A.; da Luz, J.R.D.; de Medeiros, K.S.; Sarmento, A.C.A.; Coppedè, F.; das Graças Almeida, M. Association of C677T and A1298C Polymorphisms of the MTHFR Gene with Maternal Risk for Down Syndrome: A Meta-Analysis of Case-Control Studies. Mutat. Res./Rev. Mutat. Res. 2023, 792, 108470. [Google Scholar] [CrossRef]
  42. Li, Y.; Pei, Y.X.; Wang, L.N.; Liang, C.; Tang, Y.L.; Zhang, X.L.; Huang, L.B.; Luo, X.Q.; Ke, Z.Y. MTHFR-C677T Gene Polymorphism and Susceptibility to Acute Lymphoblastic Leukemia in Children: A Meta-Analysis. Crit. Rev. Eukaryot. Gene Expr. 2020, 30, 125–136. [Google Scholar] [CrossRef]
  43. Frikha, R. Assessment of the Relationship between Methylenetetrahydrofolate Reductase Polymorphism and Acute Lymphoblastic Leukemia: Evidence from an Updated Meta-Analysis. J. Oncol. Pharm. Pract. 2020, 26, 1598–1610. [Google Scholar] [CrossRef]
  44. Li, S.Y.; Ye, J.Y.; Liang, E.Y.; Zhou, L.X.; Yang, M. Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies. Med. Sci. Monit. 2015, 21, 740–748. [Google Scholar] [CrossRef] [PubMed]
  45. Hasan, T.; Arora, R.; Bansal, A.K.; Bhattacharya, R.; Sharma, G.S.; Singh, L.R. Disturbed Homocysteine Metabolism Is Associated with Cancer. Exp. Mol. Med. 2019, 51, 1–13. [Google Scholar] [CrossRef] [PubMed]
  46. Kattner, P.; Strobel, H.; Khoshnevis, N.; Grunert, M.; Bartholomae, S.; Pruss, M.; Fitzel, R.; Halatsch, M.E.; Schilberg, K.; Siegelin, M.D.; et al. Compare and Contrast: Pediatric Cancer versus Adult Malignancies. Cancer Metastasis Rev. 2019, 38, 673–682. [Google Scholar] [CrossRef] [PubMed]
  47. Alejandro Sweet-Cordero, E.; Biegel, J.A. The Genomic Landscape of Pediatric Cancers: Implications for Diagnosis and Treatment. Science 2019, 363, 1170–1175. [Google Scholar] [CrossRef] [PubMed]
  48. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ 2021, 372, 71. [Google Scholar] [CrossRef]
  49. Stang, A. Critical Evaluation of the Newcastle-Ottawa Scale for the Assessment of the Quality of Nonrandomized Studies in Meta-Analyses. Eur. J. Epidemiol. 2010, 25, 603–605. [Google Scholar] [CrossRef]
  50. Cumpston, M.S.; McKenzie, J.E.; Welch, V.A.; Brennan, S.E. Strengthening Systematic Reviews in Public Health: Guidance in the Cochrane Handbook for Systematic Reviews of Interventions, 2nd Edition. J. Public Health 2022, 44, E588–E592. [Google Scholar] [CrossRef]
  51. Cochrane Handbook for Systematic Reviews of Interventions|Cochrane Training. Available online: https://training.cochrane.org/handbook/current (accessed on 22 December 2024).
  52. Kamel, A. Synergistic Effect of Methyltetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphism as Risk Modifiers of Pediatric Acute Lymphoblastic Leukemia. J. Egypt. Natl. Canc Inst. 2007, 19, 96–105. [Google Scholar]
  53. Gong, Y.; Luo, L.; Wang, L.; Chen, J.; Chen, F.; Ma, Y.; Xu, Z.; Sun, Y.; Luo, L.; Shi, C.; et al. Association of MTHFR and ABCB1 Polymorphisms with MTX-Induced Mucositis in Chinese Paediatric Patients with Acute Lymphoblastic Leukaemia, Lymphoma or Osteosarcoma-A Retrospective Cohort Study. J. Clin. Pharm. Ther. 2021, 46, 1557–1563. [Google Scholar] [CrossRef]
  54. Choi, R.; Sohn, I.; Kim, M.J.; Woo, H.I.; Lee, J.W.; Ma, Y.; Yi, E.S.; Koo, H.H.; Lee, S.Y. Pathway Genes and Metabolites in Thiopurine Therapy in Korean Children with Acute Lymphoblastic Leukaemia. Br. J. Clin. Pharmacol. 2019, 85, 1585–1597. [Google Scholar] [CrossRef]
  55. Mostafa-Hedeab, G.; Elborai, Y.; Ebid, G.T.A. Effects of Methylene Tetrahydro Folate Reductase Gene Polymorphisms on Methotrexate Toxicity in Egyptian Pediatric Acute Lymphocytic Leukaemia Patients. Iran. J. Pharm. Res. 2020, 19, 387–393. [Google Scholar] [CrossRef] [PubMed]
  56. Zheng, M.M.; Yue, L.J.; Zhang, H.H.; Yang, C.L.; Xie, C. Association of Single Nucleotide Polymorphism of Methylenetetrahydrofolate Reductase Gene with Susceptibility to Acute Leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2013, 30, 451–455. [Google Scholar] [CrossRef]
  57. Frikha, R.; Turki, F.; Frikha, F.; Elloumi, M.; Rebai, T. Involvement of MTHFR Rs1801133 in the Susceptibility of Acute Lymphoblastic Leukemia: A Preliminary Study. J. Pediatr. Hematol. Oncol. 2021, 43, E816–E818. [Google Scholar] [CrossRef] [PubMed]
  58. Hur, M.; Park, J.Y.; Cho, H.C.; Lee, K.M.; Shin, H.Y.; Cho, H.I. Methylenetetrahydrofolate Reductase A1298C Genotypes Are Associated with the Risks of Acute Lymphoblastic Leukaemia and Chronic Myelogenous Leukaemia in the Korean Population. Clin. Lab. Haematol. 2006, 28, 154–159. [Google Scholar] [CrossRef] [PubMed]
  59. Stewart, A.; Sun, C.; Ding, D.; Wen, Z.; Zhang, C.; Kong, J. Association between Micronutrients and Hyperhomocysteinemia: A Case-Control Study in Northeast China. Nutrients 2023, 15, 1895. [Google Scholar] [CrossRef]
  60. Waggiallah, H.A.; Mohieldeen, W.A.; Ahmed, A.; Elmosaad, Y.M.; Suliman, R.S.; Alfahed, A.; Hjazi, A.; Al Shmrany, H.; Hakami, N.; Hakami, M.A.; et al. Detection of Methylene Tetrahydrofolate Reductase (MTHFR C677T) Mutation among Acute Lymphoblastic Leukemia in Sudanese Patients. Rep. Biochem. Mol. Biol. 2023, 12, 458. Available online: http://rbmb.net/article-1-1260-en.html&sw=Detection+of+Methylene+Tetrahydrofolate+Reductase+%28mthfr+C677t%29+Mutation+Among+Acute+LymphoLymphob+Leukemia+in+Sudanese+Patients (accessed on 23 December 2024).
  61. Jiang, N.; Zhu, X.; Zhang, H.; Wang, X.; Zhou, X.; Gu, J.; Chen, B.; Ren, J. The Relationship between Methylenetetrahydrofolate Reductase Polymorphism and Hematological Malignancy. Clin. Lab. 2014, 60, 767–774. [Google Scholar] [CrossRef]
  62. Carvalho, D.C.; Wanderley, A.V.; Mello Junior, F.A.R.; dos Santos, A.M.R.; Leitão, L.P.C.; de Souza, T.P.; de Castro, A. de N.C.L.; de Magalhães, L.L.; Fernandes, M.R.; de Carvalho Junior, J.A.N.; et al. Association of Genes ARID5B, CEBPE and Folate Pathway with Acute Lymphoblastic Leukemia in a Population from the Brazilian Amazon Region. Leuk. Res. Rep. 2019, 13, 100188. [Google Scholar] [CrossRef]
  63. Chung-Filho, A.A.; Brisson, G.D.; Vieira, T.M.F.; Chagas-Neto, P.; Soares-Lima, S.C.; Pombo-de-Oliveira, M.S. MTHFR Rs1801133 Polymorphism Is Associated with Increased Risk of B-Cell Precursor Lymphoblastic Leukaemia with Recurrent Genetic Aberrations of Fetal Origin. Cancer Epidemiol. 2020, 65, 101693. [Google Scholar] [CrossRef]
  64. Vu Hoang, P.T.; Ambroise, J.; Dekairelle, A.F.; Durant, J.F.; Butoescu, V.; Dang Chi, V.L.; Huynh, N.; Nguyen, T.B.; Robert, A.; Vermylen, C.; et al. Comparative Pharmacogenetic Analysis of Risk Polymorphisms in Caucasian and Vietnamese Children with Acute Lymphoblastic Leukemia: Prediction of Therapeutic Outcome? Br. J. Clin. Pharmacol. 2015, 79, 429–440. [Google Scholar] [CrossRef]
  65. Alcasabas, P.; Ravindranath, Y.; Goyette, G.; Haller, A.; Del Rosario, L.; Lesaca-Medina, M.Y.; Darga, L.; Ostrea, E.M.; Taub, J.W.; Everson, R.B. 5,10-Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and the Risk of Acute Lymphoblastic Leukemia (ALL) in Filipino Children. Pediatr. Blood Cancer 2008, 51, 178–182. [Google Scholar] [CrossRef] [PubMed]
  66. Azhar, M.R.; Rahimi, Z.; Vaisi-Raygani, A.; Akramipour, R.; Madani, H.; Rahimi, Z.; Parsian, A. Lack of Association between MTHFR C677T and A1298C Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia in the Kurdish Population from Western Iran. Genet. Test. Mol. Biomark. 2012, 16, 198–202. [Google Scholar] [CrossRef] [PubMed]
  67. Bahari, G.; Hashemi, M.; Naderi, M.; Taheri, M. Association between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Susceptibility to Childhood Acute Lymphoblastic Leukemia in an Iranian Population. Int. J. Hematol. Oncol. Stem Cell Res. 2016, 10, 130. [Google Scholar] [PubMed]
  68. Balta, G.; Yuksek, N.; Ozyurek, E.; Ertem, U.; Hicsonmez, G.; Altay, C.; Gurgey, A. Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 Genotypes in Childhood Acute Leukemia. Am. J. Hematol. 2003, 73, 154–160. [Google Scholar] [CrossRef]
  69. Bohanec, G.P.; Jazbec, J.; Dolẑan, V. Gene-Gene Interactions in the Folate Metabolic Pathway Influence the Risk for Acute Lymphoblastic Leukemia in Children. Leuk. Lymphoma 2007, 48, 786–792. [Google Scholar] [CrossRef]
  70. Chan, J.Y.S.; Ugrasena, D.G.; Lum, D.W.K.; Lu, Y.; Yeoh, A.E.J. Xenobiotic and Folate Pathway Gene Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukaemia in Javanese Children. Hematol. Oncol. 2011, 29, 116–123. [Google Scholar] [CrossRef]
  71. Chatzidakis, K.; Goulas, A.; Athanassiadou-Piperopoulou, F.; Fidani, L.; Koliouskas, D.; Mirtsou, V. Methylenetetrahydrofolate Reductase C677T Polymorphism: Association with Risk for Childhood Acute Lymphoblastic Leukemia and Response during the Initial Phase of Chemotherapy in Greek Patients. Pediatr. Blood Cancer 2006, 47, 147–151. [Google Scholar] [CrossRef]
  72. Damnjanovic, T.; Milicevic, R.; Novkovic, T.; Jovicic, O.; Bunjevacki, V.; Jekic, B.; Lukovic, L.; Novakovic, I.; Redzic, D.; Milasin, J. Association between the Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Acute Lymphoblastic Leukemia in Serbian Children. J. Pediatr. Hematol. Oncol. 2010, 32, e148–e150. [Google Scholar] [CrossRef]
  73. De Jonge, R.; Tissing, W.J.E.; Hooijberg, J.H.; Jansen, G.; Kaspers, G.J.L.; Lindemans, J.; Peters, G.J.; Pieters, R. Polymorphisms in Folate-Related Genes and Risk of Pediatric Acute Lymphoblastic Leukemia. Blood 2009, 113, 2284–2289. [Google Scholar] [CrossRef]
  74. Feng, Y.; Wu, J. Relationship between Genetic Polymorphism of Methylenetetrahydrfolate Reductase and the Risk of Childhood Acute Lymphocytic Leukemia. J. Leuk. Lymphoma 2012, 12, 736–738. [Google Scholar] [CrossRef]
  75. Franco, R.F.; Simões, B.P.; Tone, L.G.; Gabellini, S.M.; Zago, M.A.; Falcão, R.P. The Methylenetetrahydrofolate Reductase C677T Gene Polymorphism Decreases the Risk of Childhood Acute Lymphocytic Leukaemia. Br. J. Haematol. 2001, 115, 616–618. [Google Scholar] [CrossRef] [PubMed]
  76. Giovannetti, E.; Ugrasena, D.G.; Supriyadi, E.; Vroling, L.; Azzarello, A.; de Lange, D.; Peters, G.J.; Veerman, A.J.P.; Cloos, J. Methylenetetrahydrofolate Reductase (MTHFR) C677T and Thymidylate Synthase Promoter (TSER) Polymorphisms in Indonesian Children with and without Leukemia. Leuk. Res. 2008, 32, 19–24. [Google Scholar] [CrossRef] [PubMed]
  77. Gómez-Gómez, Y.; Organista-Nava, J.; Villanueva-Flores, F.; Estrada-Brito, J.S.; Rivera-Ramírez, A.B.; Saavedra-Herrera, M.V.; Jiménez-López, M.A.; Illades-Aguiar, B.; Leyva-Vázquez, M.A. Association Between the 5,10-MTHFR 677C>T and RFC1 80G>A Polymorphisms and Acute Lymphoblastic Leukemia. Arch. Med. Res. 2019, 50, 175–180. [Google Scholar] [CrossRef] [PubMed]
  78. Gutiérrez-Álvarez, O.; Lares-Asseff, I.; Galaviz-Hernández, C.; Reyes-Espinoza, E.A.; Almanza-Reyes, H.; Sosa-Macías, M.; Chairez Hernández, I.; Salas-Pacheco, J.M.; Bailón-Soto, C.E. Involvement of MTHFR and TPMT Genes in Susceptibility to Childhood Acute Lymphoblastic Leukemia (ALL) in Mexicans. Drug Metab. Pers. Ther. 2016, 31, 41–46. [Google Scholar] [CrossRef] [PubMed]
  79. Van Den Heuvel-eibrink, M. Germline Variation in the MTHFR and MTRR Genes Determines the Nadir of Bone Density in Pediatric Acute Lymphoblastic Leukemia: A Prospective Study. Bone 2011, 48, 571–577. [Google Scholar]
  80. Kałuzna, E.M.; Strauss, E.; Światek-Kościelna, B.; Zajac-Spychała, O.; Gowin, E.; Nowak, J.S.; Rembowska, J.; Januszkiewicz-Lewandowska, D. The Methylenetetrahydrofolate Reductase 677T-1298C Haplotype Is a Risk Factor for Acute Lymphoblastic Leukemia in Children. Medicine 2017, 96, e9290. [Google Scholar] [CrossRef]
  81. Karathanasis, N.V.; Stiakaki, E.; Goulielmos, G.N.; Kalmanti, M. The Role of the Methylenetetrahydrofolate Reductase 677 and 1298 Polymorphisms in Cretan Children with Acute Lymphoblastic Leukemia. Genet Test Mol. Biomark. 2011, 15, 5–10. [Google Scholar] [CrossRef]
  82. Kim, N.K.; Chong, S.Y.; Jang, M.J.; Hong, S.H.; Kim, H.S.; Cho, E.K.; Lee, J.A.; Ahn, M.J.; Kim, C.S.; Oh, D. Association of the Methylenetetrahydrofolate Reductase Polymorphism in Korean Patients with Childhood Acute Lymphoblastic Leukemia. Anticancer. Res. 2006, 26, 2879–2881. [Google Scholar]
  83. Krajinovic, M.; Lamothe, S.; Labuda, D.; Lemieux-Blanchard, É.; Théorêt, Y.; Moqhrabi, A.; Sinnett, D. Role of MTHFR Genetic Polymorphisms in the Susceptibility to Childhood Acute Lymphoblastic Leukemia. Blood 2004, 103, 252–257. [Google Scholar] [CrossRef]
  84. Kreile, M.; Rots, D.; Piekuse, L.; Cebura, E.; Grutupa, M.; Kovalova, Z.; Lace, B. Lack of Association between Polymorphisms in Genes MTHFR and MDR1 with Risk of Childhood Acute Lymphoblastic Leukemia. Asian Pac. J. Cancer Prev. 2014, 15, 9707–9711. [Google Scholar] [CrossRef]
  85. Li, X.; Liao, Q.; Zhang, S.; Chen, M. Association of Methylenetetrahytrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms with the Susceptibility of Childhood Acute Lymphoblastic Leukaemia (ALL) in Chinese Population. Eur. J. Med. Res. 2014, 19, 5. [Google Scholar] [CrossRef] [PubMed]
  86. Lightfoot, T.J.; Johnston, W.T.; Painter, D.; Simpson, J.; Roman, E.; Skibola, C.F.; Smith, M.T.; Allan, J.M.; Taylor, G.M. Genetic Variation in the Folate Metabolic Pathway and Risk of Childhood Leukemia. Blood 2010, 115, 3923–3929. [Google Scholar] [CrossRef] [PubMed]
  87. Metayer, C.; Scélo, G.; Chokkalingam, A.P.; Barcellos, L.F.; Aldrich, M.C.; Chang, J.S.; Guha, N.; Urayama, K.Y.; Hansen, H.M.; Block, G.; et al. Genetic Variants in the Folate Pathway and Risk of Childhood Acute Lymphoblastic Leukemia. Cancer Causes Control 2011, 22, 1243–1258. [Google Scholar] [CrossRef] [PubMed]
  88. Milne, E.; Greenop, K.R.; Scott, R.J.; Haber, M.; Norris, M.D.; Attia, J.; Jamieson, S.E.; Miller, M.; Bower, C.; Bailey, H.D.; et al. Folate Pathway Gene Polymorphisms, Maternal Folic Acid Use, and Risk of Childhood Acute Lymphoblastic Leukemia. Cancer Epidemiol. Biomark. Prev. 2015, 24, 48–56. [Google Scholar] [CrossRef]
  89. Mosaad, Y.M.; Abousamra, N.K.; Elashery, R.; Fawzy, I.M.; Eldein, O.A.S.; Sherief, D.M.; El Azab, H.M.M. Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism and Susceptibility to Acute Lymphoblastic Leukemia in a Cohort of Egyptian Children. Leuk. Lymphoma 2015, 56, 2699–2705. [Google Scholar] [CrossRef]
  90. Nikbakht, M.; MalekZadeh, K.; Kumar Jha, A.; Askari, M.; Marwaha, R.K.; 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. [Google Scholar]
  91. Oliveira, E.; Alves, S.; Quental, S.; Ferreira, F.; Norton, L.; Costa, V.; Amorim, A.; Prata, M.J. The MTHFR C677T and A1298C Polymorphisms and Susceptibility to Childhood Acute Lymphoblastic Leukemia in Portugal. J. Pediatr. Hematol. Oncol. 2005, 27, 425–429. [Google Scholar] [CrossRef]
  92. Pei, J.S.; Hsu, C.M.; Tsai, C.W.; Chang, W.S.; Ji, H.X.; Hsiao, C.L.; Miao, C.E.; Hsu, Y.N.; Bau, D.T. The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan. PLoS ONE 2015, 10, e0119776. [Google Scholar] [CrossRef]
  93. Reddy, H.; Jamil, K. Polymorphisms in the MTHFR Gene and Their Possible Association with Susceptibility to Childhood Acute Lymphocytic Leukemia in an Indian Population. Leuk. Lymphoma 2006, 47, 1333–1339. [Google Scholar] [CrossRef]
  94. Sadananda Adiga, M.N.; Chandy, S.; Ramachandra, N.; Appaji, L.; Aruna Kumari, B.S.; Ramaswamy, G.; Savithri, H.S.; Krishnamoorthy, L. Methylenetetrahydrofolate Reductase Gene Polymorphisms and Risk of Acute Lymphoblastic Leukemia in Children. Indian J. Cancer 2010, 47, 40–45. [Google Scholar] [CrossRef]
  95. Schnakenberg, E.; Mehles, A.; Cario, G.; Rehe, K.; Seidemann, K.; Schlegelberger, B.; Elsner, H.A.; Welte, K.H.; Schrappe, M.; Stanulla, M. Polymorphisms of Methylenetetrahydrofolate Reductase (MTHFR) and Susceptibility to Pediatric Acute Lymphoblastic Leukemia in a German Study Population. BMC Med. Genet. 2005, 6, 23. [Google Scholar] [CrossRef] [PubMed]
  96. Silva, R.M.S.; Fontes, A.C.L.; Silva, K.A.; Sant’Ana, T.A.; Ramos, F.J.D.C.; Marques-Salles, T.D.J.; Pombo-De-Oliveira, M.S.; Muniz, M.T.C. Polymorphisms Involved in Folate Metabolism Pathways and the Risk of the Development of Childhood Acute Leukemia. Genet. Test. Mol. Biomark. 2013, 17, 147–152. [Google Scholar] [CrossRef]
  97. Sood, S.; Das, R.; Trehan, A.; Ahluwalia, J.; Sachdeva, M.U.; Varma, N.; Bansal, D.; Marwaha, R.K. Methylenetetrahydrofolate Reductase Gene Polymorphisms: Association with Risk for Pediatric Acute Lymphoblastic Leukemia in North Indians. Leuk. Lymphoma 2010, 51, 928–932. [Google Scholar] [CrossRef] [PubMed]
  98. Thirumaran, R.K.; Gast, A.; Flohr, T.; Burwinkel, B.; Bartram, C.; Hemminki, K.; Kumar, R.; Sinnett, D.; Labuda, D.; Krajinovic, M. MTHFR Genetic Polymorphisms and Susceptibility to Childhood Acute Lymphoblastic Leukemia. Blood 2005, 106, 2590–2591. [Google Scholar] [CrossRef] [PubMed]
  99. Tong, N.; Fang, Y.; Li, J.; Wang, M.; Lu, Q.; Wang, S.; Tian, Y.; Rong, L.; Sun, J.; Xu, J.; et al. Methylenetetrahydrofolate Reductase Polymorphisms, Serum Methylenetetrahydrofolate Reductase Levels, and Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population. Cancer Sci. 2010, 101, 782–786. [Google Scholar] [CrossRef] [PubMed]
  100. Wiemels, J.L.; Smith, R.N.; Taylor, G.M.; Eden, O.B.; Alexander, F.E.; Greaves, M.F. Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Risk of Molecularly Defined Subtypes of Childhood Acute Leukemia. Proc. Natl. Acad. Sci. USA 2001, 98, 4004–4009. [Google Scholar] [CrossRef]
  101. Xia, X.; Duan, Y.; Cui, J.; Jiang, J.; Lin, L.; Peng, X.; Wang, Y.H.; Guo, B.; Liu, S.; Lei, X. Association of Methylenetetrahydrofolate Reductase Gene-Gene Interaction and Haplotype with Susceptibility to Acute Lymphoblastic Leukemia in Chinese Children. Leuk. Lymphoma 2017, 58, 1887–1892. [Google Scholar] [CrossRef]
  102. Yeoh, A.E.J.; Lu, Y.; Chan, J.Y.S.; Chan, Y.H.; Ariffin, H.; Kham, S.K.Y.; Quah, T.C. Genetic Susceptibility to Childhood Acute Lymphoblastic Leukemia Shows Protection in Malay Boys: Results from the Malaysia-Singapore ALL Study Group. Leuk. Res. 2010, 34, 276–283. [Google Scholar] [CrossRef]
  103. Zanrosso, C.W.; Hatagima, A.; Emerenciano, M.; Ramos, F.; Figueiredo, A.; Félix, T.M.; Segal, S.L.; Giugliani, R.; Muniz, M.T.C.; Pombo-De-Oliveira, M.S. The Role of Methylenetetrahydrofolate Reductase in Acute Lymphoblastic Leukemia in a Brazilian Mixed Population. Leuk. Res. 2006, 30, 477–481. [Google Scholar] [CrossRef]
  104. Zou, R.; He, X.; Wu, Y.; Tian, X.; You, Y.; Zheng, M.; Li, W.; Zou, H.; Liu, H.; Zhu, X.; et al. TS Gene Polymorphisms Correlate with Susceptibility to Acute Lymphocytic Leukemia in Children. Med. Sci. Monit. 2017, 23, 3095–3104. [Google Scholar] [CrossRef]
  105. da Costa Ramos, F.J.; Cartaxo Muniz, M.T.; Silva, V.C.; Araújo, M.; Leite, E.P.; Freitas, E.M.; Zanrosso, C.W.; Hatagima, A.; de Mello, M.P.; Yunes, J.A.; et al. Association between the MTHFR A1298C Polymorphism and Increased Risk of Acute Myeloid Leukemia in Brazilian Children. Leuk. Lymphoma 2006, 47, 2070–2075. [Google Scholar] [CrossRef] [PubMed]
  106. Bolufer, P.; Collado, M.; Barragán, E.; Cervera, J.; Calasanz, M.J.; Colomer, D.; Roman-Gómez, J.; Sanz, M.A. The Potential Effect of Gender in Combination with Common Genetic Polymorphisms of Drug-Metabolizing Enzymes on the Risk of Developing Acute Leukemia. Haematologica 2007, 92, 308–314. [Google Scholar] [CrossRef] [PubMed]
  107. Sirachainan, N.; Wongruangsri, S.; Kajanachumpol, S.; Pakakasama, S.; Visudtibhan, A.; Nuchprayoon, I.; Lusawat, A.; Phudhicharoenrat, S.; Shuangshoti, S.; Hongeng, S. Folate Pathway Genetic Polymorphisms and Susceptibility of Central Nervous System Tumors in Thai Children. Cancer Detect. Prev. 2008, 32, 72–78. [Google Scholar] [CrossRef] [PubMed]
  108. Salnikova, L.E.; Belopolskaya, O.B.; Zelinskaya, N.I.; Rubanovich, A.V. The Potential Effect of Gender in CYP1A1 and GSTM1 Genotype-Specific Associations with Pediatric Brain Tumor. Tumour Biol. 2013, 34, 2709–2719. [Google Scholar] [CrossRef]
  109. Greenop, K.R.; Scott, R.J.; Attia, J.; Bower, C.; De Klerk, N.H.; Norris, M.D.; Haber, M.; Jamieson, S.E.; Van Bockxmeer, F.M.; Gottardo, N.G.; et al. Folate Pathway Gene Polymorphisms and Risk of Childhood Brain Tumors: Results from an Australian Case-Control Study. Cancer Epidemiol. Biomark. Prev. 2015, 24, 931–937. [Google Scholar] [CrossRef] [PubMed]
  110. De Miranda, D.O.; Barros, J.E.X.S.; Vieira, M.M.S.; Lima, E.L.S.; Moraes, V.L.L.; Da Silva, H.A.; Garcia, H.L.B.O.; Lima, C.A.; Gomes, A.V.; Santos, N.; et al. Reduced Folate Carrier-1 G80a Gene Polymorphism Is Associated with Neuroblastoma’s Development. Mol. Biol. Rep. 2014, 41, 5069–5075. [Google Scholar] [CrossRef]
  111. De Lima, E.L.S.; Da Silva, V.C.; Da Silva, H.D.A.; Bezerra, A.M.; De Morais, V.L.L.; De Morais, A.L.; Cruz, R.V.; Barros, M.H.M.; Hassan, R.; De Freitas, A.C.; et al. MTR Polymorphic Variant A2756G and Retinoblastoma Risk in Brazilian Children. Pediatr. Blood Cancer 2010, 54, 904–908. [Google Scholar] [CrossRef]
  112. Soleimani, E.; Saliminejad, K.; Akbari, M.T.; Kamali, K.; Ahani, A. Association Study of the Common Polymorphisms in the Folate-Methionine Pathway with Retinoblastoma. Ophthalmic Genet. 2016, 37, 384–387. [Google Scholar] [CrossRef]
  113. Bisht, S.; Chawla, B.; Dada, R. Oxidative Stress and Polymorphism in MTHFR SNPs (677 and 1298) in Paternal Sperm DNA Is Associated with an Increased Risk of Retinoblastoma in Their Children: A Case–Control Study. J. Pediatr. Genet 2018, 7, 103. [Google Scholar] [CrossRef]
  114. Gohari, M.; Dastgheib, S.A.; Jafari-Nedooshan, J.; Akbarian-Bafghi, J.M.; Morovati-Sharifabad, M.; Mirjalili, R.S.; Neamatzadeh, H. Association of MTHFR 677C<T, 1298A<C and MTR 2756A<G Polymorphisms with Risk of Retinoblastoma. Klin. Onkol. 2019, 32, 375–379. [Google Scholar] [CrossRef]
  115. Stanulla, M.; Seidemann, K.; Schnakenberg, E.; Book, M.; Mehles, A.; Weite, K.; Schrappe, M.; Reiter, A. Methylenetetrahydrofolate Reductase (MTHFR) 677C>T Polymorphism and Risk of Pediatric Non-Hodgkin Lymphoma in a German Study Population. Blood 2005, 105, 906–907. [Google Scholar] [CrossRef] [PubMed]
  116. Patiño-García, A.; Zalacaín, M.; Marrodán, L.; San-Julián, M.; Sierrasesúmaga, L. Methotrexate in Pediatric Osteosarcoma: Response and Toxicity in Relation to Genetic Polymorphisms and Dihydrofolate Reductase and Reduced Folate Carrier 1 Expression. J. Pediatr. 2009, 154, 688–693. [Google Scholar] [CrossRef] [PubMed]
  117. Ferrara, M.; Capozzi, L.; Russo, R. Impact of the MTHFR C677T Polymorphism on Risk of Wilms Tumor: Case-Control Study. J. Pediatr. Hematol. Oncol. 2009, 31, 256–258. [Google Scholar] [CrossRef] [PubMed]
  118. Koppen, I.J.N.; Hermans, F.J.R.; Kaspers, G.J.L. Folate Related Gene Polymorphisms and Susceptibility to Develop Childhood Acute Lymphoblastic Leukaemia. Br. J. Haematol. 2010, 148, 3–14. [Google Scholar] [CrossRef]
  119. Yan, J.; Yin, M.; Dreyer, Z.E.; Scheurer, M.E.; Kamdar, K.; Wei, Q.; Okcu, M.F. A Meta-Analysis of MTHFR C677T and A1298C Polymorphisms and Risk of Acute Lymphoblastic Leukemia in Children. Pediatr. Blood Cancer 2012, 58, 513–518. [Google Scholar] [CrossRef]
  120. Xiao, Y.; Deng, T.R.; Su, C.L.; Shang, Z. Methylenetetrahydrofolate Reductase Polymorphisms and Susceptibility to Acute Lymphoblastic Leukemia in a Chinese Population: A Meta-Analysis. Oncol. Res. Treat. 2014, 37, 576–582. [Google Scholar] [CrossRef]
  121. Zintzaras, E.; Doxani, C.; Rodopoulou, P.; Bakalos, G.; Ziogas, D.C.; 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. [Google Scholar] [CrossRef]
  122. Zhang, B.; Zhang, W.; Yan, L.; Wang, D. The Association between MTHFR Gene C677T Polymorphism and ALL Risk Based on a Meta-Analysis Involving 17,469 Subjects. Clin. Chim. Acta 2017, 466, 85–92. [Google Scholar] [CrossRef]
  123. Lien, S.Y.A.; Young, L.; Gau, B.S.; Shiao, S.P.K. Meta-Prediction of MTHFR Gene Polymorphism-Mutations, Air Pollution, and Risks of Leukemia among World Populations. Oncotarget 2017, 8, 4387–4398. [Google Scholar] [CrossRef]
  124. Gohari, M.; Moghimi, M.; Aarafi, H.; Shajari, A.; Jafari-Nedooshan, J.; Lookzadeh, M.H.; Mirjalili, S.R.; Neamatzadeh, H. Association of MTHFR 677C>T, 1298A>C and MTR 2756A>G Polymorphisms with Susceptibility to Childhood Retinoblastoma: A Systematic Review and Met-Analysis. Fetal Pediatr. Pathol. 2021, 40, 612–625. [Google Scholar] [CrossRef]
  125. Qin, Y.T.; Zhang, Y.; Wu, F.; Su, Y.; Lu, G.N.; Wang, R.S. Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis. PLoS ONE 2014, 9, 88823. [Google Scholar] [CrossRef] [PubMed]
  126. Wang, G.; Wu, Y.; Jing, Z.; Wen, R.; Song, Y.; Feng, Y.; Li, G.; Zou, X.; Huang, G.; Jia, Z.; et al. Association of MTHFR Gene Polymorphisms with Non-Hodgkin Lymphoma Risk: Evidence from 31 Articles. J. Cancer 2024, 15, 5277–5287. [Google Scholar] [CrossRef] [PubMed]
  127. Kawami, M.; Honda, N.; Hara, T.; Yumoto, R.; Takano, M. Investigation on Inhibitory Effect of Folic Acid on Methotrexate-Induced Epithelial-Mesenchymal Transition Focusing on Dihydrofolate Reductase. Drug Metab. Pharmacokinet. 2019, 34, 396–399. [Google Scholar] [CrossRef] [PubMed]
  128. Rahmayanti, S.U.; Amalia, R.; Rusdiana, T. Systematic Review: Genetic Polymorphisms in the Pharmacokinetics of High-Dose Methotrexate in Pediatric Acute Lymphoblastic Leukemia Patients. Cancer Chemother. Pharmacol. 2024, 94, 141–155. [Google Scholar] [CrossRef]
  129. Ramalingam, R.; Kaur, H.; Scott, J.X.; Sneha, L.M.; Arunkumar, G.; Srinivasan, A.; Paul, S.F.D. Evaluation of Cytogenetic and Molecular Markers with MTX-Mediated Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients. Cancer Chemother. Pharmacol. 2022, 89, 393–400. [Google Scholar] [CrossRef]
  130. Zahra, F.T.; Nahid, N.A.; Islam, M.R.; Al-Mamun, M.M.A.; Apu, M.N.H.; Nahar, Z.; Kabir, A.L.; Biswas, S.K.; Ahmed, M.U.; Islam, M.S.; et al. Pharmacogenetic Variants in MTHFR Gene Are Significant Predictors of Methotrexate Toxicities in Bangladeshi Patients With Acute Lymphoblastic Leukemia. Clin. Lymphoma Myeloma Leuk. 2020, 20, e58–e65. [Google Scholar] [CrossRef]
  131. Razali, R.H.; Noorizhab, M.N.F.; Jamari, H.; James, R.J.; Teh, K.H.; Ibrahim, H.M.; Teh, L.K.; Salleh, M.Z. Association of ABCC2 with Levels and Toxicity of Methotrexate in Malaysian Childhood Acute Lymphoblastic Leukemia (ALL). Pediatr. Hematol. Oncol. 2020, 37, 185–197. [Google Scholar] [CrossRef]
  132. Zhang, Y.; Sun, L.; Chen, X.; Zhao, L.; Wang, X.; Zhao, Z.; Mei, S. A Systematic Review of Population Pharmacokinetic Models of Methotrexate. Eur. J. Drug Metab. Pharmacokinet. 2022, 47, 143–164. [Google Scholar] [CrossRef]
  133. Yang, F.Y.; Xu, L.H.; Wang, J.; Zhang, Y.T.; Lin, S.F.; Wang, K.M.; Zhou, D.H.; Fang, J.P. Relationship between MTHFR Gene Polymorphism(C677T) and Adverse Reactions of High-Dose Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2023, 31, 967–972. Available online: https://europepmc.org/article/MED/37551463 (accessed on 23 December 2024).
  134. Zhou, Y.; He, H.; Ding, L.; Wang, T.; Liu, X.; Zhang, M.; Zhang, A.; Fu, J. Effects of Gene Polymorphisms on Delayed MTX Clearance, Toxicity, and Metabolomic Changes after HD-MTX Treatment in Children with Acute Lymphoblastic Leukemia. Eur. J. Pediatr. 2024, 183, 581–590. [Google Scholar] [CrossRef]
  135. Chang, X.; Guo, Y.; Su, L.; Zhang, Y.; Hui, W.; Zhao, H.; Hu, R.; Sun, W. Influence of MTHFR C677T Polymorphism on High-Dose Methotrexate-Related Toxicity in Patients With Primary Central Nervous System Diffuse Large B-Cell Lymphoma. Clin. Lymphoma Myeloma Leuk. 2021, 21, 91–96. [Google Scholar] [CrossRef]
Children 12 00108 g001
Figure 1. Flow chart diagram for studies that included children and adolescents with ALL.
Figure 1. Flow chart diagram for studies that included children and adolescents with ALL.
Children 12 00108 g001
Children 12 00108 g002
Figure 2. Forest plot of the correlation of T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Figure 2. Forest plot of the correlation of T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Children 12 00108 g002
Children 12 00108 g003
Figure 3. Forest plot of the correlation of C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Figure 3. Forest plot of the correlation of C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Children 12 00108 g003
Children 12 00108 g004
Figure 4. Forest plot and subgroup analysis of the correlation of T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population based on the population’s origin. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,84,85,86,87,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Figure 4. Forest plot and subgroup analysis of the correlation of T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population based on the population’s origin. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,84,85,86,87,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Children 12 00108 g004
Children 12 00108 g005
Figure 5. Forest plot and subgroup analysis of the correlation of C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population based on the population’s origin. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,84,85,86,87,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Figure 5. Forest plot and subgroup analysis of the correlation of C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population based on the population’s origin. Each individual study is portrayed by a box (effect estimate) and a horizontal line (length of confidence interval) in the right column. The diamond shows the pooled result [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,84,85,86,87,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].
Children 12 00108 g005
Children 12 00108 g006
Figure 6. Funnel plot for the assessment of publication bias for the correlation of (a) T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population and (b) C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Individual studies are represented by circles, the blue diagonal dashed lines represent the confidence interval 95%, while the black vertical dashed line represents the overall effect.
Figure 6. Funnel plot for the assessment of publication bias for the correlation of (a) T allele sequences (CT and TT variations) of the 677C>T polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population and (b) C allele sequences (AC and CC variations) of the 1298A>C polymorphism of the MTHFR gene in children and adolescents with ALL versus a healthy population. Individual studies are represented by circles, the blue diagonal dashed lines represent the confidence interval 95%, while the black vertical dashed line represents the overall effect.
Children 12 00108 g006
Table 1. MTHFR gene polymorphisms in children and adolescents with AML versus a healthy population.
Table 1. MTHFR gene polymorphisms in children and adolescents with AML versus a healthy population.
AuthorYearCountry of OriginPatient Group (n)Control Group (n)677C>T Polymorphism1298A>C Polymorphism
CCCTTTAAACCC
Ramos [105]2006Brazil18231510.88
(0.58–1.32)		1.19
(0.62–2.27)		11.09
(0.72–1.65)		1.39
(0.66–2.93)
Bolufer [106]2007Spain355110.98
(0.64–1.50)		0.87
(0.51–1.51)		---
Lightfoot [86]2010U.K.5837810.51
(0.3–0.87)		1
(0.50–2.01)		10.67
(0.40–1.12)		1.22
(0.60–2.48)
Silva [96]2013Brazil3322411.8
(0.83–3.90)		2.1
(0.45–9.71)		10.55
(0.24–1.26)		0.33
(0.10–1.04)
Data are presented as odds ratio (confidence interval) per polymorphism.
Table 2. MTHFR gene polymorphisms in children and adolescents with CNS tumors versus a healthy population.
Table 2. MTHFR gene polymorphisms in children and adolescents with CNS tumors versus a healthy population.
AuthorYearCountry of OriginType of CancerPatient Group (n)Control Group (n)677C>T Polymorphism1298A>C Polymorphism
CCCTTTAAACCC
Sirachainan [107]2008ThailandGlial tumors +7320511.2
(0.6–2.1)		2
(0.3–12.2)		11
(0.5–1.7)		1.6
(0.6–4.3)
Salnikova [108]2013RussiaGlial and embryonic tumors ++28445610.86
(0.64–1.16)		0.80
(0.46–1.39)		---
Greenop [109]2015AustraliaNon-specified brain tumors32155210.95
(0.7–1.29)		0.83
(0.51–1.36)		10.95
(0.7–1.28)		1.24
(0.73–2.09)
De Miranda [110]2014BrazilNeuroblastoma299211.45
(0.58–3.63)		1.76
(0.37–8.18)		---
Santos de Lima [111]2010BrazilRetinoblastoma729711.76
(0.61–5.04)		1.82
(0.65–5.07)		10.99
(0.28–3.46)		1.46
(0.39–5.39)
Soleimani [112]2016IranRetinoblastoma9620410.51
(0.3–0.87)		0.23
(0.03–0.91)		11.11
(0.65–1.91)		0.72
(0.34–1.49)
Bisht [113]2018IndiaRetinoblastoma9090116.03
(8.9–28.8)		0110.2
(5.6–18.58)		0
Gohari [114]2019SloveniaRetinoblastoma669910.91
(0.48–1.70)		1.16
(0.46–2.94)		10.813
(0.41–1.5)		1.33
(0.42–4.17)
Data are presented as odds ratio (confidence interval) per polymorphism. + Astrocytoma, oligodendroglioma, ependymoma. ++ Astrocytoma, oligodendroglioma, brain stem glioma, ependymoma and medulloblastoma, primitive neuroectodermal brain tumors (PNETs), atypical teratoid rhabdoid tumors and pineoblastoma.
Table 3. MTHFR gene polymorphisms in children and adolescents with other types of cancer per category versus a healthy population.
Table 3. MTHFR gene polymorphisms in children and adolescents with other types of cancer per category versus a healthy population.
AuthorYearCountry of OriginType of CancerPatient Group (n)Control Group (n)677C>T Polymorphism1298A>C Polymorphism
CCCTTTAAACCC
Stanulla [115]2005GermanyNon-Hodgkin lymphoma 48737911.26
(0.95–1.68)		1.32
(0.86–2.04)		1--
Patîno–Garcia [116]2008SpainOsteosarcoma9611010.87
(0.47–1.6)		0.67
(0.3–1.5)		11.26
(0.7–2.3)		1.1
(0.36–3.1)
Ferrara [117]2009ItalyWilms’ tumors347011.42
(0.62–3.27)		3.22
(1.13–9.15)		1--
Data are presented as odds ratio (confidence interval) per polymorphism.
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Kolanis, S.; Kotanidou, E.P.; Tsinopoulou, V.R.; Georgiou, E.; Hatzipantelis, E.; Fidani, L.; Galli-Tsinopoulou, A. MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis. Children 2025, 12, 108. https://doi.org/10.3390/children12010108

AMA Style

Kolanis S, Kotanidou EP, Tsinopoulou VR, Georgiou E, Hatzipantelis E, Fidani L, Galli-Tsinopoulou A. MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis. Children. 2025; 12(1):108. https://doi.org/10.3390/children12010108

Chicago/Turabian Style

Kolanis, Savvas, Eleni P. Kotanidou, Vasiliki Rengina Tsinopoulou, Elisavet Georgiou, Emmanuel Hatzipantelis, Liana Fidani, and Assimina Galli-Tsinopoulou. 2025. "MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis" Children 12, no. 1: 108. https://doi.org/10.3390/children12010108

APA Style

Kolanis, S., Kotanidou, E. P., Tsinopoulou, V. R., Georgiou, E., Hatzipantelis, E., Fidani, L., & Galli-Tsinopoulou, A. (2025). MTHFR Gene Polymorphisms and Cancer Risk in Children and Adolescents: A Systematic Review and Meta-Analysis. Children, 12(1), 108. https://doi.org/10.3390/children12010108

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