SHMT1 1420C Research Articles

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation.

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation.The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.

The RFC1 80G>A, among Common One-Carbon Polymorphisms, Relates to Survival Rate According to DNA Global Methylation in Primary Liver Cancers.

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.

Nutrients and Genetic Variation Involved in One-Carbon Metabolism and Hodgkin Lymphoma Risk: A Population-based Case-Control Study

Nutritional and genetic determinants of the one-carbon metabolism pathway have been related to risk of malignant lymphomas, but little is known about their associations with Hodgkin lymphoma risk specifically. The authors examined nutrient intake (folate, vitamin B(2), vitamin B(6), vitamin B(12), methionine) and multivitamin use among 497 Hodgkin lymphoma patients and 638 population-based controls (Massachusetts and Connecticut, 1997-2000), and genetic variation (MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, SHMT1 1420C>T, TYMS 1494del6) and gene-diet interactions in a subset. Unconditional logistic regression was used to calculate multivariable odds ratios and 95% confidence intervals. Hodgkin lymphoma risk was not associated with total nutrient intake or intake from food alone (excluding supplements). Multivitamin use (odds ratio (OR) = 1.46, 95% CI: 1.09, 1.96), total vitamin B(6) (OR(quartile 4 vs. 1) = 1.62) (P(trend) = 0.03), and total vitamin B(12) (OR(quartile 4 vs. 1) = 1.75) (P(trend) = 0.02) intakes were positively associated with risk of Epstein-Barr virus-negative, but not -positive, disease. The 5 genetic variants were not significantly associated with Hodgkin lymphoma risk; no significant gene-diet interactions were observed after Bonferroni correction. Study findings do not support a strong role for nutrients and genetic variation in the one-carbon metabolism pathway in susceptibility to Hodgkin lymphoma. Associations between diet and risk of Epstein-Barr virus-negative disease require confirmation in other populations.

Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults

The present study examined the associations between genetic variation in folate metabolism on the one hand and cognitive functioning and mood on the other in healthy individuals. Two independent population-based samples were used, including 777 participants, aged 24-82 years, from the Maastricht Aging Study (MAAS); and 818 participants, aged 50-70 years, from the Folic Acid and Carotid Intima-Media Thickness (FACIT) study. Thymidylate synthase (TS) 2R→3R and serine hydroxymethyltransferase (SHMT1) 1420C→T polymorphisms were determined in both populations. In addition, the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism was determined in the MAAS population. Cognitive performance was assessed in both populations using a neuropsychological test battery. In the MAAS population only, cognitive performance was retested after 12years of follow-up (n=612), and mood was measured at baseline (n=772) and 12-year follow-up (n=565) by means of the depression subscale of the Symptom Checklist 90. We found that in both study populations, cognitive performance was not associated with TS 2R→3R or SHMT1 1420C→T polymorphisms at baseline, after correction for age, sex, and level of education. The MTHFR 677C→T polymorphism was not associated with cognitive performance in the MAAS population. None of the polymorphisms in the MAAS population were related to mood at baseline or over 12 years. In conclusion, our findings do not support the involvement of genetic variation in folate metabolism in cognitive performance or mood in healthy individuals.

Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese

Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCR–restriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.19–3.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.06–4.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.25–0.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.41–0.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.40–0.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.97–40.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.12–0.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate-related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese.

Associations of Folate, Vitamin B12, Homocysteine, and Folate-Pathway Polymorphisms with Prostate-Specific Antigen Velocity in Men with Localized Prostate Cancer

Vitamin B(12), holo-haptocorrin, and the folate-pathway single-nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer. We measured plasma folate, B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K.-wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements. Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in log(e) concentration, 1.57; 95% confidence interval (95% CI), 0.98-2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y. We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer. Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication.

Association of Folate-Pathway Gene Polymorphisms with the Risk of Prostate Cancer: a Population-Based Nested Case-Control Study, Systematic Review, and Meta-analysis

Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer.

Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia

AbstractPolymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS −151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS −151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P < .05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS −151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS −151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G>A and NNMT IVS −151C>T variants to an increased ALL susceptibility.

Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia

AbstractWe studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI50, cont) or short-term (3 hours; TSI50, short) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI50, cont. In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL. (Blood. 2005;106:717-720)