Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes.
ABSTRACT Because little is known about the etiology of non-Hodgkin lymphoma (NHL), a heterogeneous disease, and because dietary factors are modifiable, the authors examined the associations between nutrients related to one-carbon metabolism and risk of NHL in a population-based case-control study of Connecticut women diagnosed between 1996 and 2000. A total of 594 cases and 710 controls completed a food frequency questionnaire for determination of intakes of folate, vitamins B(2), B(6), and B(12), and methionine. Through unconditional logistic regression, the authors estimated the risk of NHL associated with intake of each nutrient. Comparing the highest quartile of intake with the lowest, the authors found lower risks of all NHL associated with increasing intakes of folate and methionine. Analysis by NHL subtype indicated lower risks of diffuse large B-cell lymphoma (highest quartile vs. lowest: odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.30, 0.98; p-trend = 0.02) and marginal zone lymphoma (highest quartile vs. lowest: OR = 0.08, 95% CI: 0.02, 0.26; p-trend < 0.0001) associated with folate. Vitamin B(6) intake was also associated with lower risk of NHL overall and of marginal zone lymphoma (highest quartile vs. lowest: OR = 0.23, 95% CI: 0.08, 0.65; p-trend = 0.002). These findings suggest that these nutrients may be important for susceptibility to NHL.
SourceAvailable from: Caroline F Bull[Show abstract] [Hide abstract]
ABSTRACT: The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30nM, 300nM or 3000nM folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30nM) cultures was 26% longer than that of 3000nM-FA cultures, however, this was followed by rapid telomere attrition over the subsequent 28 days (p-trend p<0.0001); both long and short telomere status was positively correlated with biomarkers of chromosome instability (p≤0.003) and mitotic dysfunction (p=0.01), measured by the cytokinesis-block micronucleus cytome assay. The early increase in TL was associated with FA-deficiency-induced global DNA hypomethylation (p=0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. qPCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = -0.47, p = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency-induced telomere dysfunction or deletion. PNA-FISH analysis showed FA-deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (p=0.0001). Together these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability.Cancer Prevention Research 11/2013; 7(1). DOI:10.1158/1940-6207.CAPR-13-0264
[Show abstract] [Hide abstract]
ABSTRACT: Corroborating evidence related to the role of aberrations on one-carbon metabolism (OCM) genes has been inconsistent. We evaluated the association between polymorphisms in 12 single nucleotide polymorphisms (SNPs) in 8 OCM genes (CBS, FPGS, FTHFD, MTRR, SHMT1, SLC19A1, TCN1, and TYMS), and non-Hodgkin lymphoma (NHL) risk in a multi-ethnic population which includes Malay, Chinese and Indian ethnic subgroups. Cases (N = 372) and controls (N = 722) were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects showed a significantly enhanced NHL risk for CBS Ex9 + 33C > T (T versus C: OR 1.55, 95 % CI 1.22-1.96, P = 0.0003), CBS Ex18-319G > A (A versus G: OR 1.15, 95 % CI 1.14-1.83; P = 0.002), SHMT1 Ex12 + 236 T > C (T versus C: OR 1.44, 95 % CI 1.15-1.81, P = 0.002), and TYMS Ex8 + 157C > T (T versus C: OR 1.29, 95 % CI 1.06-1.57, P = 0.01). Haplotype analysis for CBS SNPs showed a significantly decreased risk of NHL in subjects with haplotype CG (OR 0.69, 95 % CI 0.56-0.86, P = <0.001). The GG haplotype for the FTHFD SNPs showed a significant increased risk of NHL (OR 1.40, 95 % CI 1.12-1.76, P = 0.002). For the TYMS gene, haplotype CAT at TYMS (OR 0.67, 95 % CI 0.49-0.90, P = 0.007) was associated with decreased risk of NHL, while haplotype TAC (OR 1.29, 95 % CI 1.05-1.58, P = 0.01) was found to confer increased risk of NHL. Our study suggests that variation in several OCM genes (CBS, FTHFD, SHMT1, TCN1, and TYMS) may influence susceptibility to NHL.Tumor Biology 11/2014; DOI:10.1007/s13277-014-2785-0
[Show abstract] [Hide abstract]
ABSTRACT: An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22-3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56-10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18-2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL.Journal of Human Genetics advance online publication, 20 March 2014; doi:10.1038/jhg.2014.19.Journal of Human Genetics 03/2014; 59(5). DOI:10.1038/jhg.2014.19