The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism Decreases Risk of Childhood Acute Lymphoblastic Leukemia (ALL): A Study of the Chinese and Malay Population.

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been implicated in childhood acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta-analyses were not adequate. In a meta-analysis of 21 publications with 4,706 cases and 7,414 controls, we used more stringent inclusion method and summarized data on associations between MTHFR C677T and A1298C polymorphisms and childhood ALL risk. We found an overall association between 677T variant genotypes and reduced childhood ALL risk. Specifically, in the dominant genetic model, an association was found in a fixed-effect (TT + CT vs. CC: OR = 0.92; 95% CI = 0.85-0.99) but not random-effect model, whereas such an association was observed in both homozygote genetic model (TT vs. CC: OR = 0.80; 95% CI = 0.70-0.93 by fixed effects and OR = 0.78; 95% CI = 0.65-0.93 by random effects) and recessive genetic model (TT vs. CC + CT: OR = 0.83; 95% CI = 0.72-0.95 by fixed effects and OR = 0.84; 95% CI = 0.73-0.97 by random effects). These associations were also observed in subgroups by ethnicity: for Asians in all models except for the dominant genetic model by random effect and for Caucasians in all models except for the recessive genetic model. However, the A1298C polymorphism did not appear to have an effect on childhood ALL risk. These results suggest that the MTHFR C677T, but not A1298C, polymorphism is a potential biomarker for childhood ALL risk.

The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC/CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (+/-4.38) in cases and 9.27 ng/mL (+/-4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population.

There is evidence supporting a role for 5-10 methylenetetrahydrofolate reductase (MTHFR) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimate of the effect of MTHFR polymorphisms on the risk of ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymorphisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity and both Egger and Begg-Mazumdar tests were used to assess publication bias. The meta-analysis of the C677T polymorphism and risk of childhood ALL included 13 studies with a total of 4,894 individuals. Under a fixed-effects model, the TT genotype failed to be associated with a statistically significant reduction of childhood ALL risk (TT versus CT + CC: OR, 0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homozygous for the 677T allele exhibited a 2.2-fold decrease in risk of adult ALL (TT versus CT + CC: OR, 0.45; 95% CI, 0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed. Our findings support the proposal that the common genetic C677T polymorphism in the MTHFR contributes to the risk of adult ALL, but not to the childhood ALL susceptibility.

Update on Diagnosis of Childhood Acute Lymphoblastic Leukemia (ALL) in Indonesia

Objective To investigate the relationship between genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) and the risk of childhood acute lymphocytic leukemia (ALL).Methods 45 patients with ALL and a cohort of 45 matched healthy children were included,and DNA was extracted from their peripheral blood.PCR-RFLP was used to determine the genotypes of MTHFR C677T and A1298C.The adjusted odds tatio (OR) and 95 ％ confidence interwal (CI) were calculated using unconditional logistic regression model.Results The frequency of MTHFR 677 CC,CT and TT genetypes were 31.1％ (14/45),51.1％ (23/45) and 17.7 ％ (8/45) in controls and 51.1％ (23/45),40.0 ％ (18/45) and 8.9 ％ (4/45)in ALL,respectively (x2 =7.48,P =0.04).The frequency of MTHFR 677 T allele were 69.9 ％ (31/45) in controls and 48.8 ％ (22/45) in ALL.The MTHFR 677 T allele had an decreased risk in ALL compared with CC genetype (OR =0.4,95 ％ CI 0.21-0.83).The frequency of MTHFR 1298 AA,AC and CC genetypes were 57.8 ％,40.0 ％ and 2.2 ％ in controls and 18.8 ％,44.4 ％ and 6.8 ％ in ALL,respectively (x2 =11.23,P=0.23).The frequency of MTHFR 1298 C allele were 51.1％ (23/45) in controls and 42.2 ％ (19/45) in ALL.No significant association between the MTHFR 1298 polymorphism and the risk of ALL (OR =1.3,95 ％ CI 0.21-0.83).Conclusion MTHFR 677 polymorphism could significantly decrease the risk of developing childhood ALL,whereas MTHFR 1298 don' t significantly affect the risk of ALL. Key words: Leukemia, lymphocytic, acute; Methylenetetrahydrofolate reductase; Polymorphisms,single nucleotide

BackgroundRecently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk.MethodsA meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used.ResultsSignificant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (ORadditive model = 1.501, 95% CI 1.112–2.026, POR = 0.008; ORdominant model = 1.316, 95% CI = 1.104–1.569, POR = 0.002) and Asian subgroup analyses (ORadditive model = 2.338, 95%CI = 1.254–4.359, POR = 0.008; ORdominant model = 2.108, 95%CI = 1.498–2.967, POR = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found.ConclusionsThe meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population.

Genetic Polymorphisms in the Folate Pathway and Risk of Childhood Acute Lymphoblastic Leukemia (ALL): MTHFR, MTHFD1, RFC1 and TS.

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) and childhood acute lymphoblastic leukemia (ALL) is inconsistent. To explore the relationship between MTHFR-C677T polymorphism and susceptibility to childhood ALL. PubMed, EMBASE, Web of Science, CNKI, Wanfang, VIP, and other databases were searched from the establishment of the database to November 2019, and all the case-control studies that met the inclusion criteria were collected. Stata 15.0 was used for meta-analysis, with calculation of the odds ratio (OR) of the relationship between MTHFR-C677T polymorphism and childhood ALL susceptibility. Ethnicity was analyzed by subgroup analysis. A total of 26 studies were included in this meta-analysis, including 4,682 children with ALL and 7144 controls. The results showed that there was no significant difference in the comparison of population of allele model, dominant gene model, recessive gene model, homozygous gene model, heterozygous gene model, and the comparison of Caucasian children. The results of the Asian child analysis suggested that the combined OR of the dominant gene model (CC + CT versus TT), homozygous model (CC versus TT) and heterozygous model (CT versus TT) was 1.32 (95% confidence interval [CI]: 1.03-1.70), 1.37 (95% CI: 1.02-1.84), and 1.27 (95% CI: 1.01-1.59), respectively, with statistically significant differences. However, there was no significant difference between the allele model and recessive gene model among Asian children. The MTHFR C677T polymorphism is related to ALL in children, especially in Asian children. CC + CT, CC, and CT genotypes can increase the risk of ALL, but no association has been found in Caucasian children.

Birth weight and other perinatal characteristics and childhood leukemia in California

Methylene tetrahydrofolate reductase C677T polymorphism in Korean livedoid vasculopathy patients

The type III receptor tyrosine kinase FLT3 is of importance in hematopoiesis. FLT3 is a frequently mutated gene in acute myeloid leukemia (AML) as well as prognostic marker. The most common mutation that occurs in patients includes internal tandem duplication (ITD) in the juxtamembrane domain. Point mutations in the kinase domain are also identified in many patients. These mutations result in constitutive activation of receptor as well as uncontrolled activation of survival pathways. Although 30 % of AML patients carry a mutation in FLT3 [2], its expression is not limited to only those patients. It has also been found to be expressed in acute lymphoblastic leukemia (ALL) and several studies identified FLT3 mutations in a portion of ALL patients. This study will identify possible correlation in between FLT3 and childhood ALL patients. With the search criteria depicted in Fig. 1a, we retrieved 12 references that included 1,213 childhood ALL patients with 76 patients (6.3 %) carrying FLT3 mutations (Table S1). All 12 studies described FLT3 mutations. Further review of those references identified 89 patients with MLL-rearrangement and 196 patients with hyperdiploid ALL. Although 6.3 % childhood ALL patients carried FLT3 mutations, 15.7 % of MLL-rearrangement and 14.4 % of hyperdiploid childhood ALL patients carried FLT3 mutations (data not shown). Only 1 % patients carried FLT3-ITD mutations (12/1,213). Childhood ALL patients with MLL-rearrangement displayed an overall odds ratio of 4.17 (95 % Cl = 2.60–9.88, p 0.0001) (Fig. 1b) and patients with hyperdiploid ALL showed an overall odds ratio of 4.03 (95 % Cl = 2.18–7.95, p 0.0001) (Fig. 1c). Studies with FLT3-ITD mutation (Fig. 1d) and FLT3-TKD mutations (Fig. 1e) showed that TKD mutations happened more frequently than ITD mutations. An increased rate of FLT3 mutations was observed in American population (odds ratio = 1.4, 95 % CI = 0.85–2.29), while in Japanese and European population, comparatively lower FLT3 mutations were identified (Fig. 1f). The receptor tyrosine kinase FLT3 is frequently mutated in AML and activating FLT3 mutations cause poor prognosis in this disease [2]. Several FLT3 inhibitors display promising results in clinical trials. Although several studies described presence of FLT3 mutations in childhood ALL, still we have limited knowledge in defining roles of FLT3 mutations. In this study, we carried out a meta-analysis to define the role of FLT3 mutations in childhood ALL. All 12 studies analyzed in this study were mainly from three different populations that cover 1,213 childhood ALL patients. The identification of 76 mutations in these populations suggests that FLT3 mutations in childhood ALL is less frequent than that of in AML. Although about 30 % of FLT3-ITD mutations were reported in AML [2], childhood ALL patients carry only 1 % FLT3-ITD mutations suggesting that targeting FLT3-ITD will not be beneficial in pediatric ALL. It is likely that mutations other than FLT3ITD mutations are more frequent, e. g. FLT3-TKD mutations. However, it is quite difficult to suggest a correlation between FLT3 mutations and ALL prognosis due to the Electronic supplementary material The online version of this article (doi:10.1007/s12032-013-0462-6) contains supplementary material, which is available to authorized users.

The Molecular Landscape of KMT2A-Rearranged Leukemia from Infancy to Adulthood Reveals Age and Leukemia-Specific Mutational Patterns

Dysregulation of microRNAs (miRNAs) targeting genes in the PI3K/Akt pathway has been implicated in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). However, the impact of genetic variants in these miRNAs on ALL susceptibility has not been extensively explored in the Chinese population. To address this gap, we conducted a case-control study to evaluate the association between genetic variants in five PI3K/AKT pathway-related miRNAs (miR-149, miR-126, miR-492, miR-612, and miR-423) and childhood ALL susceptibility in the Chinese population. Additionally, we investigated the effects of the rs2292832 mutation on ALL cell proliferation and apoptosis. Our analyses revealed that the miR-149 rs2292832 mutant heterozygous CT genotype was more frequent in the control group than in the ALL cases, indicating a protective effect against ALL (adjusted odds ratio [OR]=0.78, 95% confidence interval [CI]=0.63-0.97, p=.024). Stratification analyses further revealed that the miR-149 rs2292832 CC genotype was associated with an increased risk of childhood ALL in subgroups of older children, females, those with parents who never smoked or drank alcohol, those living in painted houses, those with B-ALL, and those with high-risk ALL. Finally, we observed that the rs2292832 mutation inhibited ALL cell proliferation and induced apoptosis (p=.001), providing a potential mechanism by which this genetic variant may influence ALL susceptibility. Our study highlights the significant association between the miR-149 rs2292832 genetic variant and childhood ALL susceptibility in the Chinese population. These findings expand our understanding of the complex genetic landscape underlying ALL and have implications for the development of personalized therapeutic strategies.