vitamin-b-12 and Colorectal-Neoplasms

This meta-analysis aimed to assess the association between vitamin B6 intake, blood PLP levels, and the risk of colorectal cancer.. The databases PubMed, Cochrane Library and Embase databases were comprehensively searched for cohort studies or case-control studies. The odds ratio (OR) and 95% confidence interval (CI) were extracted from each eligible study, and the statistical software Stata was used to perform statistical merging.. Twenty-eight studies (20 cohort studies, 8 case-control studies) were included in our meta-analysis. The combined OR for the association between colorectal cancer risk and vitamin B6 intake was 0.80 (95% CI: 0.68-0.94), while the combined OR between blood PLP levels and colorectal cancer risk was 0.54 (95% CI: 0.35-0.84). In addition, the subgroup analysis revealed that vitamin B6 could reduce the risk of colorectal cancer in women [vitamin B6 intake OR = 0.79, 95% CI (0.65-0.96); blood PLP levels OR = 0.41, 95% CI (0.30-0.57)] and also reduce the risk of colon cancer in men and women [vitamin B6 intake OR = 0.76, 95% CI (0.64-0.91); blood PLP levels OR = 0.56, 95% CI (0.42-0.73)].. In this meta-analysis, vitamin B6 intake and blood PLP levels were inversely associated with colorectal cancer risk.

Topics: Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Female; Humans; Male; Nutritional Status; Observational Studies as Topic; Risk; Vitamin B 12; Vitamin B 6

Meat is an important food for human nutrition, by especially providing high-quality protein and also some essential micronutrients, in front iron, zinc, and vitamin B

Topics: Animals; Cardiovascular Diseases; Cattle; Colorectal Neoplasms; Diabetes Mellitus, Type 2; Diet, Healthy; Dietary Proteins; Evidence-Based Medicine; Food, Preserved; Humans; Iron, Dietary; Meat; Meat Products; Meta-Analysis as Topic; Mortality; Nutritive Value; Risk Factors; Sheep, Domestic; Sus scrofa; Vitamin B 12; Zinc

The current meta-analysis evaluated the association between vitamin B12 intake and blood vitamin B12 level and colorectal cancer (CRC) risk.. The PubMed and EMBASE databases were searched. A dose-response analysis was performed with generalized least squares regression, with the relative risk (RR) and 95 % CI as effect values.. The meta-analysis included seventeen studies.. A total of 10 601 patients.. The non-linear dose-response relationship between total vitamin B12 intake and CRC risk was insignificant (P=0·690), but the relationship between dietary vitamin B12 intake and CRC risk was significant (P<0·001). Every 4·5 μg/d increment in total and dietary vitamin B12 intake was inversely associated with CRC risk (total intake: RR=0·963; 95 % CI 0·928, 0·999; dietary intake: RR=0·914; 95 % CI 0·856, 0·977). The inverse association between vitamin B12 intake and CRC risk was also significant when vitamin B12 intake was over a dosage threshold, enhancing the non-linear relationship. The non-linear dose-response relationship between blood vitamin B12 level and CRC risk was insignificant (P=0·219). There was an insignificant association between every 150 pmol/l increment in blood vitamin B12 level and CRC risk (RR=1·023; 95 % CI 0·881, 1·187).. Our meta-analysis indicates that evidence supports the use of vitamin B12 for cancer prevention, especially among populations with high-dose vitamin B12 intake, and that the association between CRC risk and total vitamin B12 intake is stronger than between CRC risk and dietary vitamin B12 intake only.

Topics: Colorectal Neoplasms; Diet; Humans; Risk Factors; Vitamin B 12

Lower levels of dietary folate are associated with the development of epithelial cell tumours in man, particularly colo-rectal cancer. In the majority of epidemiological studies blood folate or reported folate intake have been shown to be inversely related to colo-rectal cancer risk. Folate, via its pivotal role in C1 metabolism, is crucial both for DNA synthesis and repair, and for DNA methylation. This function is compromised when vitamin B12 is low. Vitamin B12 deficiency has been shown to increase biomarkers of DNA damage in man but there is no evidence directly linking low vitamin B12 with cancer. Disturbingly, folate and vitamin B12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How folate and/or vitamin B12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instability in the DNA molecule via a futile cycle of uracil misincorporation and removal. The relative importance of these two pathways may become clear by determining both DNA stability and cytosine methylation in individuals with different polymorphic variants of key folate-metabolising enzymes. 5,10-Methylenetetrahydrofolate reductase converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and thereby controls whether folate is employed for DNA synthesis or DNA methylation. Colo-rectal cancer risk is decreased in subjects homozygous for a common variant (C677T) of the gene coding for this enzyme, suggesting that DNA synthesis and repair may be 'enhanced' in these individuals. Evidence from animal and human studies is presented here in support of folate acting to maintain genomic stability through both these mechanisms.

Topics: Carbon-Nitrogen Ligases; Colorectal Neoplasms; DNA Damage; DNA Methylation; DNA Repair; Folic Acid; Folic Acid Deficiency; Gene Expression Regulation, Neoplastic; Humans; Polymorphism, Genetic; Proto-Oncogene Mas; Risk Factors; Vitamin B 12; Vitamin B 12 Deficiency

Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.. To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.. We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.. Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.. Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis

Topics: Ascorbic Acid; Avitaminosis; Blood Coagulation; Breast Neoplasms; Carotenoids; Chronic Disease; Colorectal Neoplasms; Coronary Disease; Dietary Supplements; Female; Folic Acid; Fractures, Bone; Humans; Lung Neoplasms; Male; Neoplasms; Neural Tube Defects; Prostatic Neoplasms; Risk Factors; Vitamin A; Vitamin B 12; Vitamin B 6; Vitamin D; Vitamin E; Vitamin K; Vitamins

The purpose of this review is to outline the principal mechanisms involved in folate metabolism and how they may relate to the pathogenesis of colorectal cancer (CRC). In recent years, mild folate depletion (low normal level) has been associated with an increased risk of developing certain cancers, in particular colorectal neoplasia. The epidemiologic and mechanistic evidence linking folate deficiency with carcinogenesis is reviewed, with a particular emphasis on colorectal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is a critical folate metabolizing enzyme, and a functional polymorphic variant of this enzyme, the so-called thermolabile variant, caused by a C677T transition in the MTHFR gene, is common in the general population. This review critically examines the evidence that suggests that carriers of this C677T variant may be at increased risk of developing colorectal neoplasia. Although folate depletion may predispose to the initiation of the neoplastic process, folate supplementation, on the other hand, might potentiate the progression of an already established early neoplastic clone (eg, a colorectal adenoma). This could have potential public health implications, given an increasingly widespread policy of folate supplementation of food staples.

Topics: Adenoma; Animals; Colorectal Neoplasms; Dietary Supplements; DNA Methylation; DNA, Neoplasm; Folic Acid; Folic Acid Deficiency; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Vitamin B 12

Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial.. Long-term follow-up of B-PROOF trial participants (. Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53,. Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer.. Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.

Topics: Aged; Aged, 80 and over; Colorectal Neoplasms; Dietary Supplements; Double-Blind Method; Female; Folic Acid; Follow-Up Studies; Humans; Incidence; Male; Neoplasms; Netherlands; Osteoporotic Fractures; Vitamin B 12

Folic acid, vitamin B(6), and vitamin B(12) act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma.. The Women's Antioxidant and Folic Acid Cardiovascular Study was a randomized, double-blind, placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005. Participants were randomly assigned to receive a combination pill of folic acid (2.5mg), vitamin B(6) (50mg), and vitamin B(12) (1mg) or placebo. This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up. We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors. All statistical tests were two-sided.. The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B(6), or vitamin B(12).. Our results indicate no statistically significant effect of combined folic acid, vitamin B(6), and vitamin B(12) treatment on colorectal adenoma among women at high risk for cardiovascular disease.

Topics: Adenoma; Adult; Aged; Anticarcinogenic Agents; Cardiovascular Diseases; Colorectal Neoplasms; Double-Blind Method; Drug Therapy, Combination; Female; Folic Acid; Follow-Up Studies; Humans; Incidence; Linear Models; Male; Middle Aged; Poisson Distribution; Risk Assessment; Risk Factors; Vitamin B 12; Vitamin B 6

Folate, other vitamin B cofactors, and genes involved in folate-mediated one-carbon metabolism all may play important roles in colorectal neoplasia. In this study, we examined the associations between dietary and circulating plasma levels of vitamins B(2), B(6), and B(12) and risk colorectal adenomas.. The Aspirin/Folate Polyp Prevention Study is a randomized clinical trial of folic acid supplementation and incidence of new colorectal adenomas in individuals with a history of adenomas (n = 1,084). Diet and supplement use were ascertained through a food frequency questionnaire administered at baseline. Blood collected at baseline was used to determine plasma B-vitamin levels. We used generalized linear regression to estimate risk ratios (RR) and 95% confidence intervals (95% CI) as measures of association.. We found a borderline significant inverse association with plasma B(6) [pyridoxal 5'-phosphate (PLP)] and adenoma risk (adjusted RR Q4 versus Q1, 0.78; 95% CI, 0.61-1.00; P(trend) = 0.08). This association was not modified by folic acid supplementation or plasma folate. However, the protective association of PLP with adenoma risk was observed only among subjects who did not drink alcohol (P(interaction) = 0.03). Plasma B(2) (riboflavin) was inversely associated with risk of advanced lesions (adjusted RR Q4 versus Q1, 0.51; 95% CI, 0.26-0.99; P(trend) = 0.12). No significant associations were observed between adenoma risk and plasma vitamin B(12) or dietary intake of vitamin B(2) and B(6). When we examined specific gene-B-vitamin interactions, we observed a possible interaction between methylenetetrahydrofolate reductase -C677T and plasma B(2) on risk of all adenomas.. Our results suggest that high levels of PLP and B(2) may protect against colorectal adenomas.

Topics: Adenoma; Alcohol Drinking; Aspirin; Chemoprevention; Colorectal Neoplasms; Double-Blind Method; Female; Folic Acid; Genotype; Humans; Incidence; Linear Models; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Neoplasm Recurrence, Local; Poisson Distribution; Polymorphism, Genetic; Riboflavin; Risk; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

Pemetrexed, an antifolate involved in purine and pyrimidine formation, is a potential alternative to fluoropyrimidines in the treatment of colorectal cancer. A phase I trial was performed to establish the maximum tolerated dose (MTD) of pemetrexed and oxaliplatin when B(12) and folate supplementation is used.. Patients with metastatic colorectal cancer received folate (> 350 microg) daily and vitamin B(12) (1000 microg) every 9 weeks starting 7 days before chemotherapy. Pemetrexed over 10 minutes and oxaliplatin over 2 hours were given every 3 weeks in escalating dose cohorts.. Twenty-two patients were entered on 6 dose levels. The MTD was established at the highest dose level, pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2). Toxicities related to treatment at the MTD included grade 3 neutropenia and thrombocytopenia. For all dose levels combined, grade 3/4 toxicities included hematologic, neurologic, and gastrointestinal. Nine of 21 evaluable patients responded overall (response rate, 43%). The time to tumor progression was 11.9 months.. The MTD was determined to be pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2) every 21 days when folate and B (12) supplementation are used. Because of the observed tolerability and activity of this regimen, further evaluation is warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Survival Rate; Treatment Outcome; Vitamin B 12

Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/microg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/microg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; DNA Methylation; Erythrocytes; Female; Folic Acid; Genotype; Homocysteine; Humans; Intestinal Mucosa; Male; Middle Aged; Oxidoreductases Acting on CH-NH Group Donors; Promoter Regions, Genetic; Uracil; Vitamin B 12

We measured plasma total homocysteine (tHcy) in 14 patients (13 patients with colorectal cancer and 1 patient with breast cancer) during their first treatment with 5-fluorouracil (5-FU) plus leucovorin [LV (5-FULV)]. Eight of these patients were investigated a second time after 3-10 cycles (median, 4 cycles) with 5-FULV. Each cycle consisted of two administrations of 5-FU (500 mg/m2) and LV (60 mg/m2) given 24 h apart. The first administration of 5-FULV on day 1 of the first cycle induced a rapid reduction of the tHcy level from 12.5 micromol/liter (10.4-15.1 micromol/liter; geometric mean with 95% confidence interval of the mean) to 9.1 micromol/liter (7.5-11.1 micromol/liter) in 24 h. tHcy remained stable at this level after the second administration of 5-FULV. In addition, the 5-FULV regimen caused a concurrent 4-fold increase in both serum and erythrocyte folate. The fifth cycle with 5-FULV had only marginal effects on the tHcy level. 5-FU without LV modulation had no effect on the plasma tHcy or folate status in eight breast cancer patients. Our data establish the reduction of tHcy as a responsive indicator of LV pharmacodynamics.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colorectal Neoplasms; Creatinine; Erythrocytes; Female; Fluorouracil; Folic Acid; Homocysteine; Humans; Leucovorin; Male; Middle Aged; Vitamin B 12

The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.. To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).. Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.. Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.. These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

Topics: Case-Control Studies; Colorectal Neoplasms; Dietary Supplements; Genetic Predisposition to Disease; Humans; Mendelian Randomization Analysis; Micronutrients; Risk Factors; Selenium; Vitamin B 12; White People

Vitamin B12 has been widely related to methionine metabolism, which is an essential component for biological methylation reactions, including DNA methylation. However, the relationship between vitamin B12 and DNA methylation is still controversial. In addition, there is increasing evidence for the association between vitamin B12 and the risk of colorectal cancer (CRC), although results of this association need to be assessed with caution. For this purpose, we hypothesized that serum vitamin B12 could be associated with global DNA methylation in the CRC context. To test this hypothesis, we studied the association between global DNA methylation through long interspersed nuclear element-1 (

Topics: Aged; Colonic Neoplasms; Colorectal Neoplasms; DNA Methylation; Epigenomics; Female; Humans; Leukocytes, Mononuclear; Logistic Models; Long Interspersed Nucleotide Elements; Male; Middle Aged; Multivariate Analysis; Spain; Vitamin B 12

One-carbon metabolism biomarkers are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs. We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre) and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk. Furthermore, the relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1,190 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5'-phosphate and riboflavin. Associations with CRC risk were estimated using conditional logistic regression. We found that the ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. In addition, associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high vs. low B-vitamin status). In conclusion, ratio-based B-vitamin markers were good predictors of total B-vitamin status and displayed similar associations as total B-vitamin status with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice.

Topics: Betaine; Biomarkers, Tumor; Carbon; Case-Control Studies; Colorectal Neoplasms; Creatinine; Cysteine; Female; Folic Acid; Homocysteine; Humans; Male; Middle Aged; Nutritional Status; Pyridoxal Phosphate; Riboflavin; Vitamin B 12; Vitamin B Complex

Colorectal cancer (CRC) is distinctive for its strikingly high correlation with the diet. Heme-iron from red and processed meat was found to strongly increase the risk of CRC, yet only 20% of the total dietary iron is heme-iron. However, the results are still inconclusive in terms of the total dietary iron and CRC risk. On the other hand, vitamin B12 has been proposed as cytoprotector, and iron and vitamin B12 share their dietary sources. Meat and animal-derived products are the only foods that naturally provide vitamin B12. While iron is abundant in a variety of foods, its bioavailability (i.e. utilization) is the highest from meat and animal foods. We hypothesize that specific combinations of foods of animal origin could alter the risk of CRC, and even modulate the progression of CRC, by simultaneously altering iron and vitamin B12. All cells are iron dependent but iron's metabolism is one of the most complex, and tightly regulated. No nutrient has so many dietary factors that inhibit its bioavailability which results in almost 80% of all dietary iron ending in the feces, which is 10-fold higher than in most tissues. Luminal exposure to iron, which was found to affect crypt fission and increases the risk of CRC, is influenced by colonic transit time, the composition of feces, and the pH in the large bowel. Therefore, "inactivating" iron in the feces by specific dietary inhibitors disables adverse alterations during the luminal exposure. Only one inhibitor has the ability to bind both forms of iron, heme and non-heme to insoluble complexes, calcium. Milk and dairy as the best dietary sources of calcium contain vitamin B12 of the highest bioavailability. While calcium (both dietary and supplemental) has been studied separately on the risk of CRC, it has not been considered from the aspect of iron bioavailability or supplying vitamin B12. Preliminary, the hypothesis was tested on the diet quality assessment in adults from two Croatia's regions with distinctive dietary characteristics and CRC risk. Diet in the first region is considered to increase the risk of CRC (e.g. high intake of red and processed meat), while a traditional Mediterranean pattern prevails in the second region. However, CRC incidence rate is higher in the second region. Comparison of the regions showed that in the first region adults have significantly higher intake of vitamin B12, and as expected, the highest contribution is from meat. Still, the contribution of milk and dairy is signif

Topics: Animals; Biological Availability; Calcium; Carcinogenesis; Colorectal Neoplasms; Diet; Disease Progression; Female; Heme; Humans; Hydrogen-Ion Concentration; Iron; Male; Milk; Models, Theoretical; Risk Factors; Vitamin B 12

Besides irreplaceable role in health, vitamin B. An observational study on 200 healthy adults from Eastern Croatia was conducted during April-May 2013. A typical diet of this population in this region is characterized with all known major dietary risk factors for CRC placing the population at high risk for CRC, yet the incidence of CRC remains relatively low.. Diet and lifestyle characteristics of 52.2% of participants can be classified as the high-risk for CRC. Women, people in lower BMI category, and urban residents have significantly lower risk of the high-risk diet and lifestyle. Higher intake of vitamin B. Higher intake of vitamin B

Topics: Adult; Colorectal Neoplasms; Croatia; Diet; Female; Humans; Life Style; Male; Risk Factors; Vitamin B 12

Liver metastatic disease is the main cause of death in colorectal cancer (CRC) patients. During metastatic spread of the disease an imbalance in the oxidative stress and inflammation plays a crucial role in tumor progression. In order to improve the efficacy of current therapies, new complementary therapeutic approaches are being analyzed including biologically active compounds with low side effects. The anti-inflammatory and anti-oxidant properties of Ocoxin® oral solution (OOS) prompt us to analyze its effect on the metastatic development of CRC to the liver. First, in vitro effect of OOS in tumor cell viability and migration was analyzed. Second, in vivo effect of different dosage patterns and concentrations in the development of hepatic metastasis was analyzed by intra-splenic inoculation of C26 colon carcinoma cells in Balb/c mice. Third, the expression of alpha smooth muscle actin, caspase-3 and Ki-67 expression was quantified by immunohistochemistry, then gene expression levels of inflammatory factors were measured by quantitative RT-PCR. According to our results, OOS reduced tumor cell viability and migration in vitro. Moreover, in vivo daily administration of OOS from the 7th day after tumor cell inoculation decreased the total area and size of metastatic foci in the liver. Furthermore, cell proliferation and fibroblast recruitment was decreased in tumor foci while a higher number of apoptotic cells were observed. Finally, RNA levels for the inflammatory mediators COX-2, IFNγ, IL1β, IL6 and TNFα were reduced in total liver. In conclusion, OOS reduced the metastatic development of colorectal cancer to the liver by increasing apoptosis, and decreasing tumor cell proliferation and fibroblast recruitment in the tumor foci, as well as the expression of inflammatory mediators in total liver. These results point out OOS as a potential supplement to be applied as complementary therapy for the treatment of liver metastasis from colorectal cancer.

Topics: Animals; Apoptosis; Ascorbic Acid; Caspase 3; Cell Proliferation; Colorectal Neoplasms; Folic Acid; Gene Expression Regulation, Neoplastic; Glycyrrhizic Acid; Humans; Ki-67 Antigen; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Proteins; Pantothenic Acid; Plant Extracts; Vitamin B 12; Vitamin B 12 Deficiency; Vitamin B 6; Zinc; Zinc Sulfate

To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions.

Topics: Aged; Brazil; Carbon Cycle; Choline; Colorectal Neoplasms; Dietary Carbohydrates; Dietary Proteins; Dietary Supplements; Energy Intake; Female; Folic Acid; Humans; Male; Middle Aged; Riboflavin; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Colon; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Homocysteine; Humans; Intestinal Mucosa; Male; Metabolic Networks and Pathways; Middle Aged; Polymorphism, Genetic; Promoter Regions, Genetic; Rectum; Vitamin B 12

Although a higher consumption of alcohol, which is a methyl-group antagonist, was previously associated with colorectal cancer risk, mechanisms remain poorly understood.. We hypothesized that excess alcohol consumption might increase risk of colorectal carcinoma with hypomethylation of insulin-like growth factor 2 (IGF2) differentially methylated region-0 (DMR0), which was previously associated with a worse prognosis.. With the use of a molecular pathologic epidemiology database in 2 prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association between alcohol intake and incident colorectal cancer according to the tumor methylation level of IGF2 DMR0. Duplication-method Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. In addition, we investigated intakes of vitamin B-6, vitamin B-12, methionine, and folate as exposures.. During 3,206,985 person-years of follow-up, we identified 993 rectal and colon cancer cases with an available tumor DNA methylation status. Compared with no alcohol consumption, the consumption of ≥15 g alcohol/d was associated with elevated risk of colorectal cancer with lower levels of IGF2 DMR0 methylation [within the first and second quartiles: HRs of 1.55 (95% CI: 1.08, 2.24) and 2.11 (95% CI: 1.44, 3.07), respectively]. By contrast, alcohol consumption was not associated with cancer with higher levels of IGF2 DMR0 methylation. The association between alcohol and cancer risk differed significantly by IGF2 DMR0 methylation level (P-heterogeneity = 0.006). The association of vitamin B-6, vitamin B-12, and folate intakes with cancer risk did not significantly differ according to IGF2 DMR0 methylation level (P-heterogeneity > 0.2).. Higher alcohol consumption was associated with risk of colorectal cancer with IGF2 DMR0 hypomethylation but not risk of cancer with high-level IGF2 DMR0 methylation. The association between alcohol intake and colorectal cancer risk may differ by tumor epigenetic features.

Topics: Adult; Aged; Alcohol Drinking; Colorectal Neoplasms; DNA Methylation; Energy Intake; Epigenesis, Genetic; Ethanol; Female; Folic Acid; Follow-Up Studies; Humans; Incidence; Insulin-Like Growth Factor II; Male; Methionine; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Factors; Vitamin B 12; Vitamin B 6

B vitamins are involved in 1-carbon metabolism, which is necessary for DNA replication, DNA repair, and regulation of gene expression. Recent studies suggest inverse associations between folate and vitamin B6 intakes and colorectal cancer risk but associations with other B vitamins and methionine have not been widely studied. After following 14,645 men and 22,467 women for 15 yr on average, we ascertained 910 incident colorectal cancers. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals were estimated using Cox regression. We found some evidence of a U-shaped relationship between colon cancer risk and vitamin B6 and an inverse U-shaped relationship between rectal cancer risk and B12 (test for the quadratic trend, P = 0.005 and P = 0.0005 respectively). For colon cancer, we observed a reduced risk associated with low methionine/high folate, HR = 0.63 (0.49, 0.80) and an increased risk associated with high methionine/high folate, HR = 1.36 (1.06, 1.74) (P interaction < 0.0001). Our study suggests a U-shaped association between colon cancer risk and vitamin B6 intake and an inverse U-shaped association between rectal cancer risk and vitamin B12. Adequate folate intake might protect against colon cancer risk in those with low methionine intake.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Confidence Intervals; Diet; Female; Folic Acid; Follow-Up Studies; Humans; Male; Methionine; Middle Aged; Proportional Hazards Models; Prospective Studies; Risk Factors; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6; Vitamin B Complex

The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case-control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.

Topics: Aged; Carbon; Case-Control Studies; Colorectal Neoplasms; Diet; Female; Folic Acid; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Methionine; Mutagenesis, Insertional; Nucleotides; One-Carbon Group Transferases; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Transcobalamins; Vitamin B 12

Folate has been strongly implicated in the aetiology of colorectal cancer. However, the relationship between dietary folate intake, rectal mucosal folate status and colorectal cancer risk is uncertain. The study aimed to estimate nutrient intakes and measure systemic folate status and rectal mucosal folate concentration in people at differential risk of developing colorectal cancer.. Two hundred and twenty-eight individuals were recruited from gastroenterology clinics and subdivided into three patient groups: untreated colorectal cancer (n = 43), adenomatous polyps (n = 90) or normal bowel (n = 95). Biopsies from macroscopically normal rectal mucosa and blood were collected and used for the measurement of rectal mucosal 5-methyltetrahydrofolate (5-MeTHF) and systemic markers of folate status, respectively. Nutrient intake was estimated using a validated food frequency questionnaire.. Dietary intake variables, plasma 5-MeTHF and red cell folate and plasma homocysteine concentrations were similar in all three subject groups and 95% CI fell within normal range for each variable. Rectal mucosal 5-MeTHF concentration was higher in the normal mucosa of adenomatous polyp patients than in normal subjects (P = 0.055). Rectal mucosal 5-MeTHF was associated significantly with plasma folate (P < 0.001, r = 0.294), red cell folate (P = 0.014, r = 0.305), plasma homocysteine (P = 0.017, r = -0.163) and dietary folate intake (P = 0.036, r = 0.152).. This study demonstrates adequate folate status of patients attending gastroenterology clinics for the investigation of bowel symptoms, with no significant difference in dietary intakes or systemic folate status indices according to diagnosis. Rectal mucosal 5-MeTHF concentrations were elevated in adenomatous polyp patients, but failed to reach significance. Further studies are required to determine the biological significance of this observation.

Topics: Cohort Studies; Colorectal Neoplasms; Diet; Erythrocytes; Female; Folic Acid; Glutathione Reductase; Homocysteine; Humans; Intestinal Mucosa; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Nutrition Assessment; Nutritional Status; Risk Factors; Surveys and Questionnaires; Tetrahydrofolates; Vitamin B 12

Circulating unconjugated bilirubin (UCB) has been reported to protect against lung and colorectal cancer. The present study aimed to explore, for the first time, whether mildly elevated circulating UCB, as found in Gilbert`s syndrome (GS), is associated with changes of DNA damage. A random 76 individuals, matched for age and gender, were recruited from the general population and allocated into the GS group (UCB ≥ 17.1 µM; n = 38) or control group (UCB <17.1 µM; n = 38). Chromosomal and cytological changes were determined in lymphocytes and buccal cells using the cytokinesis-block micronucleus cytome assay (CBMN) and buccal micronucleus cytome assay (BMcyt). No significant differences were found between GS subjects and the control group in the CBMN and BMcyt determined endpoints. Subsequently, when age dependency of effects were analysed, lower formation of buccal micronucleated cells (by 73.3%) and buccal nuclear buds (by 70.9%) in the GS subgroup ≥ 30 years were found, compared to the GS subgroup <30 years. These findings suggest DNA protection in epithelial tissue of older individuals with GS.

Topics: Adult; Aged; Aged, 80 and over; Bilirubin; Chromosome Aberrations; Colorectal Neoplasms; Comet Assay; Cytokinesis; DNA Damage; Endpoint Determination; Female; Folic Acid; Gilbert Disease; Homocysteine; Humans; Lung Neoplasms; Lymphocytes; Male; Micronucleus Tests; Middle Aged; Vitamin B 12; Young Adult

Food sources and intakes of zinc and heme iron may differ between Western and Asian populations. However, all of the studies on the association between zinc and heme iron intakes and colorectal cancer have been conducted in Western populations.. We investigated the association between zinc and heme iron intakes and colorectal cancer risk in a Japanese general population.. We conducted a large, population-based prospective study in 39,721 men and 45,376 women aged 45-74 y. Heme iron and zinc intakes were measured by using a validated food-frequency questionnaire in either 1995 or 1998.. During as many as 808,053 person-years of follow-up until the end of 2006, 1284 colorectal cancer cases were identified. In multivariate-adjusted models, zinc and heme iron intakes were not associated with colorectal cancer in either men or women. In comparison with the lowest quartile, the HRs (95% CIs) for developing colorectal cancer in the fourth quartile of zinc and heme iron intakes were 0.77 (0.58, 1.03; P-trend = 0.2) and 1.06 (0.79, 1.42; P-trend = 0.6), respectively, for men and 1.05 (0.77, 1.44; P-trend = 0.4) and 0.88 (0.61, 1.29; P-trend = 0.4), respectively, for women.. Our results in a Japanese population with lower intakes and different major food sources of zinc and heme iron in comparison with those of Western populations suggest that zinc and heme iron intakes are not associated with colorectal cancer.

Topics: Adult; Aged; Alcohol Drinking; Cohort Studies; Colorectal Neoplasms; Diet; Female; Follow-Up Studies; Heme; Humans; Iron, Dietary; Japan; Male; Middle Aged; Prospective Studies; Risk; Sex Characteristics; Vitamin B 12; Vitamin B 6; Zinc

Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.

Topics: Aged; Colorectal Neoplasms; CpG Islands; DNA Methylation; Feeding Behavior; Female; Folic Acid; Follow-Up Studies; Genetic Markers; Humans; Incidence; Iowa; Life Style; Micronutrients; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Nutrition Surveys; Phenotype; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Risk Factors; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6; Women's Health

Topics: Adenoma; Anticarcinogenic Agents; Cardiovascular Diseases; Colorectal Neoplasms; Female; Folic Acid; Humans; Male; Vitamin B 12; Vitamin B 6

The clinical phenotype of cobalamin (Cbl) deficiency is dictated by the essential role of this vitamin in two key enzymatic reactions. Multiple proteins and receptors participate in the absorption, transport and delivery of this vitamin to tissue cells. Cellular uptake of Cbl is mediated by transcobalamin (TC), a plasma protein and a transmembrane receptor (TCblR) with high affinity for TC saturated with Cbl. Knockdown of TCblR with siRNA results in decreased TC-Cbl uptake. The ensuing Cbl deficiency leads to an increase in doubling time and decreased proliferation of these cells. The study confirms the seminal role of this receptor in the cellular uptake of Cbl and its down-regulation as a potential strategy to inhibit proliferation of cancer cells.

Topics: Adenocarcinoma; Antigens, CD; Blotting, Western; Cell Proliferation; Colorectal Neoplasms; Humans; Kidney; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Vitamin B 12

There are no data regarding basal folate levels in patients without colorectal adenoma. This study aimed to determine the minimum serum folate concentration that associates with reduced risk of colorectal adenoma.. 1510 consecutive patients underwent total colonoscopy for suspected colorectal lesions after barium enema examination. Prior to colonoscopy, history of alcohol consumption was noted and blood serum analyzed for folate and vitamin B12 levels. Polypoid lesions were evaluated histologically. We excluded patients with anemia, history of colonoscopy, overconsumption of alcohol, or malignancies. In all, 458/1510 patients (male/female; 258/200, 40-75 years) were determined eligible. Variables were compared between patients with adenoma and those without adenoma.. Serum folate concentration was the variable with the most significant statistical variation between males with adenoma (8.0 ng/ml) and males without adenoma (9.2) (p = 0.001). Serum folate concentrations in females with adenoma did not differ significantly from those in females without adenoma (10.7 versus 10.9). When subjects were stratified into groups according to serum folate, we found no significant difference in the prevalence of adenoma in patients with folate levels greater than 8.0 ng/ml.. Patients with serum folate concentrations above 8.0 ng/ml had the lowest risk of developing colorectal adenoma.

Topics: Adenoma; Adult; Aged; Colorectal Neoplasms; Cross-Sectional Studies; Female; Folic Acid; Folic Acid Deficiency; Hospitals, Teaching; Humans; Japan; Male; Mass Screening; Middle Aged; Prevalence; Prospective Studies; Risk; Sex Factors; Vitamin B 12; Vitamin B 12 Deficiency

Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however, the outcome appears to be dependent on timing. This study sought to determine the effect of altering folate (and related B vitamin) availability during in-utero development and the suckling period on intestinal tumorigenesis.. Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B(2), B(6), B(12) and folate for 4 weeks before mating to Apc(1638N) males. Females remained on their diet throughout pregnancy and until weaning. After weaning, all Apc(1638N) offspring were maintained on replete diets for 29 weeks.. At 8 months of age tumour incidence was markedly lower among offspring of supplemented mothers (21%) compared with those of replete (59%) and deficient (55%) mothers (p=0.03). Furthermore, tumours in pups born to deficient dams were most likely to be invasive (p=0.03). The expression of Apc, Sfrp1, Wif1 and Wnt5a--all of which are negative regulatory elements of the Wnt signalling cascade--in the normal small intestinal mucosa of pups decreased with decreasing maternal B vitamin intake, and for Sfrp1 this was inversely related to promoter methylation. β-Catenin protein was elevated in offspring of deficient dams.. These changes indicate a de-repression of the Wnt pathway in pups of deficient dams and form a plausible mechanism by which maternal B vitamin intake modulates tumorigenesis in offspring. These data indicate that maternal B vitamin supplementation suppresses, while deficiency promotes, intestinal tumorigenesis in Apc(1638N) offspring.

Topics: Animals; Animals, Newborn; Colorectal Neoplasms; Dietary Supplements; Disease Models, Animal; Female; Folic Acid; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pregnancy; Prenatal Exposure Delayed Effects; Riboflavin; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin D Deficiency; Wnt Signaling Pathway

Although critical for methylation reactions, how dietary folate and B vitamins affect global DNA methylation level in colorectal cancers is currently unknown. Long interspersed nucleotide element-1 (LINE-1) is an emerging indicator of genome-wide DNA methylation level that has previously been linked to colon cancer survival.. We examined the association between dietary intake of folate, alcohol and B vitamins and LINE-1 hypomethylation in 609 incident colon cancers, utilising the database of two independent prospective cohort studies.. Participants with > or = 400 microg folate intake per day were significantly less likely to develop LINE-1 hypomethylated colon cancers than those reporting <200 microg of folate intake per day (RR=0.57, 95% CI=0.36 to 0.91 for <55% LINE-1 methylated colon tumours; RR=0.74, 95% CI=0.51 to 1.06 for 55-64% LINE-1 methylated colon tumours; and RR=1.08, 95% CI=0.66 to 1.75 for > or = 65% LINE-1 methylated tumours; P(interaction)=0.01). By contrast, high alcohol consumption conferred a higher risk of LINE-1 hypomethylated cancers (> or = 15 g alcohol per day versus none, RR=1.67, 95% CI=1.04 to 2.67 for <55% LINE1 methylated tumours; and RR=1.55, 95% CI=1.10 to 2.18 for 55-64% LINE-1 methylated tumours) but had no association with > or = 65% LINE-1 methylated tumours (RR=1.06, 95% CI=0.69 to 1.62). High intakes of vitamin B(6), B(12) or methionine were not significantly associated with colon cancers, regardless of LINE-1 methylation level.. The influence of dietary folate intake and alcohol consumption on colon cancer risk differs significantly according to tumoral LINE-1 methylation level.

Topics: Alcohol Drinking; Colorectal Neoplasms; Diet; DNA Methylation; DNA, Neoplasm; Ethanol; Female; Folic Acid; Humans; Long Interspersed Nucleotide Elements; Male; Prospective Studies; Vitamin B 12; Vitamin B 6

We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP).. This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight.. A reduced risk of CIMP-low/CIMP-high CRC (> or =1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)].. Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.

Topics: Aged; Carbon; Case-Control Studies; Colorectal Neoplasms; CpG Islands; DNA Methylation; Female; Folic Acid; Genetic Predisposition to Disease; Homocysteine; Humans; Incidence; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Multivariate Analysis; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Sweden; Vitamin B 12

Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.. This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B(12) metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model.. In the log additive model, two linked (r(2) = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r(2) = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements.. Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users.. This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.

Topics: Case-Control Studies; Colorectal Neoplasms; Dietary Supplements; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Humans; Male; Microsatellite Instability; Middle Aged; Polymorphism, Single Nucleotide; United States; Vitamin B 12

B-vitamins are essential for one-carbon metabolism and have been linked to colorectal cancer. Although associations with folate have frequently been studied, studies on other plasma vitamins B2, B6, and B12 and colorectal cancer are scarce or inconclusive.. We carried out a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, including 1,365 incident colorectal cancer cases and 2,319 controls matched for study center, age, and sex. We measured the sum of B2 species riboflavin and flavin mononucleotide, and the sum of B6 species pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid as indicators for vitamin B2 and B6 status, as well as vitamin B12 in plasma samples collected at baseline. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for colorectal cancer were estimated using conditional logistic regression, adjusted for smoking, education, physical activity, body mass index, alcohol consumption, and intakes of fiber and red and processed meat.. The relative risks comparing highest to lowest quintile were 0.71 [95% confidence interval (95% CI), 0.56-0.91; P(trend) = 0.02] for vitamin B2, 0.68 (95% CI, 0.53-0.87; P(trend) <0.001) for vitamin B6, and 1.02 (95% CI, 0.80-1.29; P(trend) = 0.19) for vitamin B12. The associations for vitamin B6 were stronger in males who consumed ≥30 g alcohol/day. The polymorphisms were not associated with colorectal cancer.. Higher plasma concentrations of vitamins B2 and B6 are associated with a lower colorectal cancer risk.. This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer.

Topics: Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Female; Folic Acid; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Riboflavin; Risk Factors; Vitamin B 12; Vitamin B 6

Topics: Colorectal Neoplasms; Folic Acid; Follow-Up Studies; Humans; Hyperhomocysteinemia; Myocardial Infarction; Neoplasms; North America; Risk; Vitamin B 12; Vitamin B Complex

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Colorectal Neoplasms; Confounding Factors, Epidemiologic; Dietary Supplements; Female; Folic Acid; Humans; Incidence; Lung Neoplasms; Male; Neoplasms; Primary Prevention; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Selenium; United States; Vitamin B 12; Vitamin B 6; Vitamin E

Topics: Adult; Aged; Case-Control Studies; China; Colorectal Neoplasms; Diet; Female; Folic Acid; Humans; Logistic Models; Methionine; Middle Aged; Niacinamide; Proportional Hazards Models; Prospective Studies; Registries; Riboflavin; Risk; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

Vitamin B(6) may lower risk of colorectal cancer by preventing aberrations in one-carbon metabolism or by anti-inflammatory effects. We prospectively evaluated the association between plasma levels of pyridoxal 5'-phosphate (PLP; the active form of vitamin B(6)) and risk of colorectal cancer in a nested case-control study within the Physicians' Health Study. Among 14,916 men who provided blood specimens in 1982 to 1984, we identified 197 incident colorectal cancer cases through 2000 and individually matched them to 371 controls by age and smoking status. Plasma PLP levels were positively correlated with cold cereal intake and plasma levels of folate and vitamin B(12) (age- and smoking-adjusted partial correction r = 0.28-0.48) and slightly inversely correlated with body mass index (r = -0.11) and plasma levels of homocysteine, C-reactive protein, tumor necrosis factor-alpha receptor 2, and interleukin-6 (r = -0.23 to -0.14). With control for these factors and known risk factors for colorectal cancer, plasma PLP levels were significantly inversely associated with risk of colorectal cancer; compared with men in the lowest quartile, those with PLP in quartiles 2 to 4 had relative risks (95% confidence interval) of 0.92 (0.55-1.56), 0.42 (0.23-0.75), and 0.49 (0.26-0.92; P(trend) = 0.01), respectively. In conclusion, vitamin B(6) may protect against colorectal cancer independent of other one-carbon metabolites and inflammatory biomarkers.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; C-Reactive Protein; Case-Control Studies; Colorectal Neoplasms; Folic Acid; Humans; Incidence; Interleukin-6; Male; Middle Aged; Physicians; Prospective Studies; Pyridoxal Phosphate; Randomized Controlled Trials as Topic; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 6

There are conflicting results on the role of cobalamin and folate for epidemiology and carcinogenesis in colorectal cancer patients and the need of supplementation for prevention of chemotherapy toxicity.. Serum cobalamin, folate, and homocysteine were analysed before and during the treatment of 93 patients with advanced colorectal cancer (ACRC) with first-line chemotherapy treatment. This cohort was compared with a healthy control group of 224 individuals.. Patients with ACRC had similar cobalamin, folate, and homocysteine values as the healthy control group. There were no correlations between serum cobalamin, folate, and homocysteine values and objective response. There were no correlations to anaemia or other severe toxicity for cobalamin and homocysteine. A total of 12 patients had folate deficiency, and 10 of those suffered from severe toxicity (grade 3 or more). All patients had markedly increased folate values after 2 months of treatment. Folate and homocysteine did not predict patient outcome; however, patients with subclinically low cobalamin values (<300 pmol/L) had significant better overall survival and time to progression than patients with normal or high cobalamin values.. Patients with ACRC seem to have fairly adequate cobalamin and folate status before and during chemotherapy treatment. This study indicates that ACRC patients receiving chemotherapy do not need supplementation with vitamin B12 and folate. A minor portion of the patients had folate deficiency, and most of those patients had severe toxicity. Patients with subclinically low cobalamin values had surprisingly better survival.

Topics: Aged; Antineoplastic Agents; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Female; Folic Acid; Humans; Male; Middle Aged; Vitamin B 12

To evaluate joint effects of Methylentetra-hydrofolate reductase (MTHFR) C677T genotypes, and serum folate/vitamin B(12) concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients.. We examined the associations between MTHFR C677T genotype, and promoter methylation of P16, hMLH1, and hMSH2 tumor-related genes among 151 sporadic colorectal cancer patients. The promoter methylation of tumor-related genes was determined by methylation-specific PCR. Eighty six patients from whom fresh tumor samples were obtained and 81 controls were also examined for serum folate and vitamin B(12) concentrations by a commercial radioimmunoassay kit.. We found 29.1% of cases had tumors with at least one methylated gene promoter. In case-case comparison, we did not find a significant association between methylation in tumors and any single genotype. However, in comparison to controls with the CC genotype, an increased risk of tumor methylation was associated with the CT genotype (OR = 2.5; 95% CI, 1.1-5.6). In case-case comparisons, folate/vitamin B(12) levels were positively associated with tumor methylation. Adjusted odds ratios for tumor methylation in cases with high (above median) versus low (below median) serum folate/vitamin B(12) levels were 4.9 (95% CI, 1.4-17.7), and 3.9 (95% CI, 1.1-13.9), respectively. The frequency of methylated tumors was significantly higher in high methyl donor than low methyl donor group, especially in those with MTHFR CT (P = 0.01), and CT/TT (P = 0.002) genotypes, but not in those with the CC genotype (P = 1.0).. We conclude that high concentrations of serum folate/vitamin B(12) levels are associated with the risk of promoter methylation in tumor-specific genes, and this relationship is modified by MTHFR C677T genotypes.

Topics: Adaptor Proteins, Signal Transducing; Case-Control Studies; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Folic Acid; Gene Expression Regulation, Neoplastic; Genotype; Humans; Iran; Methylenetetrahydrofolate Reductase (NADPH2); MutL Protein Homolog 1; MutS Homolog 2 Protein; Nuclear Proteins; Odds Ratio; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Assessment; Vitamin B 12

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case-control study of folate intake, related dietary factors and MTHFR polymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12 or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CT v. CC = 0.77 (95 % CI 0.52, 1.16); OR for TT v. CC = 0.62 (95 % CI 0.31, 1.24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0.81 (95 % CI 0.45, 1.49)). There were significant interactions between total folate and C677T (P = 0.029) and A1298C (P = 0.025), and total vitamin B6 and both polymorphisms (C677T, P = 0.016; A1298C, P = 0.033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

Topics: Adult; Case-Control Studies; Colorectal Neoplasms; Diet; Female; Folic Acid; Genetic Predisposition to Disease; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Risk Factors; Vitamin B 12; Vitamin B 6

In this nested case-referent study, we related plasma concentrations of vitamin B12 to the risk of colorectal cancer, taking into consideration prediagnostic plasma folate and total homocysteine concentrations. Subjects were 226 cases and double matched referents from the population-based Northern Sweden Health and Disease Study. Follow-up times from recruitment to diagnosis ranged from 0.1 to 12.7 years, with a median of 4.2 years. Plasma vitamin B12 concentrations were inversely associated with the risk of rectal cancer: univariate odds ratio for the highest versus lowest quintile 0.34 (95% confidence interval (95% CI) 0.13-0.83), p(trend) = 0.004. Risk estimates were attenuated slightly but remained statistically significant after adjustment for body mass index, current smoking, recreational and occupational physical activity, alcohol intake and prediagnostic plasma folate and total homocysteine concentrations: OR 0.30 (95% CI 0.08-0.99), p(trend) = 0.025. The corresponding univariate and fully adjusted odds ratios for colon cancer were 1.25 (CI 0.66-2.36), p(trend) = 0.185 and 1.42 (CI 0.67-3.05), p(trend) = 0.113, respectively. The observed over-risk was attributable to left-sided colon cancer. Interaction analyses including vitamin B12, folate and homocysteine were in line with the results for vitamin B12 alone. In conclusion, these results suggest that increasing levels of plasma vitamin B12, alone or together with other factors involved in one-carbon metabolism, may reduce the risk of rectal cancer, whereas for colon cancer, the association appears to be less clear.

Topics: Adult; Aged; Analysis of Variance; Case-Control Studies; Colorectal Neoplasms; Female; Folic Acid; Homocysteine; Humans; Male; Middle Aged; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Sweden; Vitamin B 12

Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related molecular phenotypes of MLH1 protein expression, microsatellite instability (MSI) and BRAF mutations in patients with colorectal carcinomas. Within the Netherlands Cohort Study on diet and cancer (n = 120 852), 648 cases (367 men and 281 women) and 4059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RRs) were calculated over categories of dietary intake in case-cohort analyses. The intakes of folate, vitamin B2, methionine and alcohol were not associated with risk of tumors showing MLH1 hypermethylation, those lacking MLH1 protein expression or with MSI. Among men, we observed strong positive associations between folate and BRAF-mutated tumors (RR = 3.04 for the highest versus lowest tertile of intake, P(trend) = 0.03) and between vitamin B6 and tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, P(trend) = 0.03). Among women, the relative risks of tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of folate and vitamin B6 intake, respectively, but these did not reach statistical significance. The positive associations between folate intake and tumors harboring BRAF mutations and between vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men and may suggest that these vitamins enhance colorectal cancer risk through genetic as well as epigenetic aberrations.

Topics: Adaptor Proteins, Signal Transducing; Aged; Cohort Studies; Colorectal Neoplasms; Diet; DNA Methylation; DNA, Neoplasm; Female; Folic Acid; Humans; Male; Methionine; Microsatellite Repeats; Middle Aged; Mutation; MutL Protein Homolog 1; Netherlands; Nuclear Proteins; Phenotype; Promoter Regions, Genetic; Proto-Oncogene Proteins B-raf; Riboflavin; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

By altering both DNA methylation and nucleotide synthesis, folate metabolism is thought to contribute to colorectal carcinogenesis. We examined the role of folate metabolism in three different phenotypes of sporadic colorectal cancers (CRCs), phenotypes that were classified by the status of microsatellite instability (MSI) and chromosomal instability (CIN): MSI-H, microsatellite stability (MSS)/aneuploidy, and MSS/diploid.. A total of 195 sporadic colorectal tumors and another 195 age- and gender-matched healthy volunteers in Taipei-Veteran General Hospital and Taipei City Hospital were collected. We analyzed for MTHFR (methylenetetrahydrofolate reductase) polymorphisms (C677T, A1297C), folate, and vitamin B(12) levels. We determined MSI status and DNA ploidy with fluorescent polymerase chain reaction and flow cytometry. Relations between clinicopathological variables and molecular variables were analyzed by chi (2) tests (with Yates' correction) for categorical variables and Student's t test for numerical variables.. Folate levels (5.02+/-4.43 ng/ml) were significantly lower in cancer patients than in controls (7.22+/-4.46 ng/ml). Vitamin B(12) level was similar between cancer patients and controls. The frequency of the TT genotype of MTHFR C627T (12.3%) was slightly higher than controls (8.2%), but it did not reach statistical significance (p=0.174). Within the low-folate group (<5 ng/ml), the frequency of the TT genotype in cancer patients (14.4%) was significantly higher than in controls (4.6%). Sixteen patients who had MSI-H CRC (8.2%) had a significantly higher frequency of TT MTHFR (37.5%) and lower folate levels (3.56+/-2.41 ng/ml) than patients with MSS tumors (10.1%, 5.14+/-3.72 ng/ml). Patients with MSS/aneuploid tumors had significantly lower folate levels (4.50+/-3.06 ng/ml) than those with MSS/diploid tumors (6.69+/-4.73 ng/ml).. Folate deficiency and the MTHFR genetic polymorphism play an important role in colorectal carcinogenesis, including MSI and CI.. Folate metabolism plays an important role in colorectal carcinogenesis. We demonstrate that patients with MSI-H tumors had higher frequency of TT MTHFR C627T (37.5%), and patients with MSS/aneuploid tumor had lower folate level (4.50+/-3.06 ng/ml).

Topics: Adult; Aged; Aged, 80 and over; Aneuploidy; Case-Control Studies; Chromosomal Instability; Colorectal Neoplasms; Female; Folic Acid; Genotype; Humans; Male; Methylenetetrahydrofolate Reductase (NADPH2); Microsatellite Instability; Middle Aged; Phenotype; Polymerase Chain Reaction; Polymorphism, Genetic; Taiwan; Vitamin B 12

Thymidylate synthase and serine hydroxymethyltransferase are involved in folate metabolism. In a case-control study, including 768 cases and 709 controls, we investigated the associations between colorectal adenomas and TS tandem repeat and SHMT1 C1420T polymorphisms, and the interplay with B-vitamins. The polymorphisms were not associated with adenomas, but there was a borderline significant interaction between TS genotype and vitamin B6: the association between vitamin B6 and adenomas seemed positive in TS 3R/3R individuals, but inverse in TS 2R/2R individuals. This study does not provide evidence for a role of SHMT1 genotype in adenoma occurrence. Future research has to indicate whether the TS-B6 interplay is a real effect or a chance finding.

Topics: Adenoma; Aged; Case-Control Studies; Colorectal Neoplasms; Diet; Folic Acid; Glycine Hydroxymethyltransferase; Humans; Middle Aged; Netherlands; Polymorphism, Genetic; Riboflavin; Risk Factors; Thymidylate Synthase; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Dietary folate status appears to influence risk for colorectal cancer possibly by alterations in DNA methylation and nucleotide precursor pools. Polymorphisms (677C-->T and 1298A-->C) in methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, determines enzyme activity. The frequency of polymorphisms in the gene varies extensively in different populations. We sought to determine the association between folate status, folate metabolism, DNA methylation, tobacco, alcohol consumption, and the risk of colorectal adenomas in African Americans. Among 58 patients who underwent a clinically indicated colonoscopy, 23 patients with histology confirmed colorectal polyps and 35 patients without were recruited for a case-control study. Blood samples were collected from fasting patients for determination of serum and red blood cell (RBC) folate, homocysteine, vitamin B(12), and methylation status. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique was performed to identify the MTHFR 677 C-->T polymorphism and specific PCR was used to analyze adenomatous polyposis coli (APC) gene-promoter sequence methylation. Among 23 cases, 49 polyps (adenomatous, n = 41 and hyperplastic, n= 8) were identified. Twenty-eight (57%) of the polyps were on the left side and 21 (42%) were on the right side of the colon. There was no association between the presence of colon polyps and levels of folate (serum, RBC), vitamin B(12), or homocysteine. Forty-eight individuals (84%) were homozygous for 677 CC. Of these individuals, 18 (37.5%) had >/=1 colorectal polyps, whereas 30 (62.5%) had no polyps. Nine individuals were heterozygous for 677 CT, and 4 (44%) of these individuals had colon polyps. Eighty-eight percent of the APC gene-promoter sequences tested using peripheral blood DNA from patients were unmethylated. Among the individuals who showed APC methylation, 66% had polyps; 33% were polyp free using their blood DNA. There was highly significant association between smoking and alcohol consumption with the presence of a colon polyp (P= .0006 and P= .05, respectively). In conclusion, the lack of the 677 TT may be a significant risk factor for colon neoplasm in the African-American population. Smoking and alcohol consumption were found to be risk factors for colon polyps. APC gene-promoter sequence methylation found in peripheral blood may be an indicator of risk for polyp formation and an important screening tool.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Alcohol Drinking; Black or African American; Case-Control Studies; Colonic Polyps; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Genes, APC; Homocysteine; Humans; Male; Middle Aged; Promoter Regions, Genetic; Smoking; Tetrahydrofolates; Vitamin B 12; Vitamins

Dietary folate and alcohol consumption as well as polymorphic variants in one-carbon metabolism genes may modulate risk of colorectal adenoma through aberrant DNA methylation and altered nucleotide synthesis and repair. We assessed the association of 24 non-synonymous single nucleotide polymorphisms (nsSNPs) in 13 genes in the one-carbon metabolism pathway and risk of colorectal adenoma in 556 incident cases and 557 controls nested in the Nurses' Health Study. Most of the SNPs were not associated with risk of colorectal adenoma. We did, however, observe a modest increased risk among carriers of the transcobalamin (TCN) II 259 Pro/Arg + Arg/Arg variant (odds ratio 1.48, 95% confidence interval 1.09-2.02) for colorectal adenoma. The TCN II Pro259Arg polymorphism may affect TCN binding and transport of vitamin B(12) and thus warrants further investigation of its biological function. In addition, the methionine synthase reductase (MTRR) Arg415Cys and MTRR Ser284Thr variant carriers, also in the vitamin B(12) pathway, have suggestive associations with advanced colorectal adenoma (defined as being larger than 1 cm, villous, tubular-villous or carcinoma in situ histology). We observed significant evidence for departure from multiplicative interaction for the betaine-homocysteine methyltransferase (BHMT) Arg239Gln with dietary methyl status (based on intake of dietary folate, methionine and alcohol intake) in relation to colorectal adenoma; no such interaction was observed for the other 23 SNPs. Further investigation is required to validate the association of the polymorphisms in the one-carbon metabolic genes and risk of colorectal adenoma.

Topics: Adenoma; Adult; Alcohol Drinking; Betaine-Homocysteine S-Methyltransferase; Case-Control Studies; Colorectal Neoplasms; Diet; Female; Ferredoxin-NADP Reductase; Folic Acid; Genetics, Population; Humans; Methionine; Middle Aged; One-Carbon Group Transferases; Polymorphism, Single Nucleotide; Prospective Studies; Risk; Transcobalamins; Vitamin B 12

We investigated the association of dietary intakes of folate, vitamin B-6, vitamin B-12, and methionine with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women. A total of 81,184 subjects (38,107 men and 43,077 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1998 to the end of 2002, during which 526 cases of colorectal cancer (335 men, 191 women) were newly identified. Dietary intake of nutrients was calculated using a 138-item self-administered FFQ. We observed a significant inverse association between vitamin B-6 intake and colorectal cancer in men. Compared with the lowest quartile, the multivariate hazard ratio (95% [CI]) in the highest quartile of intake was 0.69 (0.48-0.98) (P(trend) = 0.03). Men who consumed 150 g/wk alcohol or more had twice the risk of colorectal cancer of those who drank less in the lowest quartile of vitamin B-6 intake, but risk due to alcohol intake was not higher in the highest quartile of vitamin B-6 intake. Vitamin B-6 intake and colorectal cancer were not associated in women. Folate and methionine intakes were not associated with colorectal cancer risk in men or women, but colorectal cancer risk tended to increase (P(trend) = 0.05) with increasing intake of vitamin B-12 in men. Our results support previous evidence that low vitamin B-6 intake is associated with an increased risk of colorectal cancer. In particular, a higher intake of vitamin B-6 appears beneficial in men with higher alcohol intake.

Topics: Aged; Alcoholic Beverages; Colorectal Neoplasms; Diet; Diet Surveys; Female; Folic Acid; Follow-Up Studies; Humans; Japan; Male; Methionine; Middle Aged; Prospective Studies; Risk Factors; Vitamin B 12; Vitamin B 6

Greater promoter methylation in some tumor-suppressor genes underlies most sporadic colorectal cancers and increases with age in the colon.. We tested the hypothesis that biomarkers of folate and vitamin B-12 status are associated with estrogen receptor alpha (ERalpha) and mutL homolog 1 (MLH1) promoter methylation in subjects with and without neoplasia.. Biopsies of normal-appearing colorectal mucosa from 156 subjects with and without colorectal neoplasia (disease free, n = 76; cancer, n = 28; adenoma, n = 35; hyperplastic polyps, n = 17) were obtained at colonoscopy and used to evaluate methylation in 7 CpG sites in the ERalpha promoter and 13 CpG sites in the MLH1 promoter. Blood samples were obtained for the measurement of serum and red cell folate, serum vitamin B-12, and plasma homocysteine concentrations. Methylation indexes were generated to reflect an average methylation value across all CpG dinucleotides in both ERalpha and MLH1.. The methylation indexes for ERalpha and MLH1 generally were significantly (P < 0.05) higher in subjects with neoplasia than in disease-free subjects. The ERalpha methylation index correlated negatively with serum vitamin B-12 (r = -0.239, P = 0.003) and positively with plasma homocysteine (r = 0.188, P = 0.021). Disease status (P < 0.005), age (P < 0.001), and serum vitamin B-12 concentrations (P = 0.006) were independent determinants of ERalpha promoter methylation. Serum and red cell folate concentrations had no influence on ERalpha promoter methylation.. Serum vitamin B-12 but not folate status may be associated with ERalpha promoter methylation in normal-appearing colorectal mucosa.

Topics: Adaptor Proteins, Signal Transducing; Adenoma; Aged; Base Sequence; Biomarkers; Case-Control Studies; Colon; Colonic Polyps; Colorectal Neoplasms; DNA Methylation; Erythrocytes; Estrogen Receptor alpha; Female; Folic Acid; Homocysteine; Humans; Intestinal Mucosa; Male; Middle Aged; MutL Protein Homolog 1; Nuclear Proteins; Nutritional Status; Vitamin B 12

The data reported here were obtained from the case-control arm of a large, comprehensive, population-based investigation of colorectal cancer incidence, etiology, and survival, the Melbourne Colorectal Cancer Study, conducted in Melbourne, Australia. This part of the case-control study was designed to identify dietary factors associated with colorectal cancer risk in 715 incident cases compared with 727 age/sex frequency-matched randomly chosen community controls, in which a quantitative assessment of all foods eaten was made. New data are presented on the potential of two groups of micronutrients as protective agents, namely, those involved in DNA methylation, synthesis, and repair (folate, methionine, and vitamins B6 and B12) and those with antioxidant properties (selenium, vitamins E and C, and lycopene). The adjusted odds ratios showed that for folate there was significant protection for rectal cancer in second and third quintiles of consumption but not for colon cancer, and this was similar for methionine consumption. Vitamin B6 consumption was significantly protective for both colon and rectal cancer at the higher quintiles, and this was similar for vitamin B12. Dietary selenium was significantly protective at middle quintiles of consumption at both cancer sites. Dietary vitamins E and C were statistically significantly protective for both colon and rectal cancer at all levels of consumption, and for both vitamins there was a dose-response effect of increasing protection, particularly so for colon cancer. Lycopene was not associated with colorectal cancer risk. A combined model included vitamins E, C, and B12 and selenium as micronutrients protective for colorectal cancer and folate, which, however, showed an increased risk at the highest level of consumption. These data support the proposition that a diet containing the dietary micronutrients involved in DNA methylation (folate, methionine, and vitamins B6 and B12) and some of those with antioxidant properties (selenium and vitamins E and C) may have a role to play in lowering colorectal cancer risk and also that such protection can be achieved by dietary means alone.

Topics: Antioxidants; Ascorbic Acid; Carotenoids; Case-Control Studies; Colorectal Neoplasms; Diet; Diet Surveys; DNA Methylation; Dose-Response Relationship, Drug; Female; Folic Acid; Humans; Lycopene; Male; Methionine; Micronutrients; Odds Ratio; Risk Factors; Selenium; Survival Analysis; Vitamin B 12; Vitamin B 6; Vitamin B Complex; Vitamin E; Vitamins

We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.

Topics: Adult; Aged; Aldehyde Dehydrogenase; Carbon-Nitrogen Ligases; Case-Control Studies; Colorectal Neoplasms; Diet; Dietary Fiber; DNA Methylation; Female; Ferredoxin-NADP Reductase; Folic Acid; Humans; Japan; Logistic Models; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Riboflavin; Risk Factors; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6; Vitamin B Complex

Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats. Weanling male Sprague-Dawley rats (n = 30) were divided into 2 groups and fed either a vitamin B-12-deficient diet or a similar diet containing adequate amounts of the vitamin. Rats from each group were killed at 6 and 10 wk. Uracil misincorporation into DNA was measured by GC/MS and genomic DNA methylation was measured by LC/MS. Plasma vitamin B-12 concentrations in deficient rats were below detectable limits at 6 and 10 wk; in control rats, concentrations were 0.46 +/- 0.07 and 0.42 +/- 0.10 nmol/L at those times. Although the colon total folate concentration did not differ between the groups, the proportion that was methylfolate was marginally greater in the deficient rats at 10 wk (P = 0.05) compared with control, consistent with the "methylfolate trap" that develops during vitamin B-12 deficiency. After 10 wk, the colonic DNA of the deficient rats displayed a 35% decrease in genomic methylation and a 105% increase in uracil incorporation (P < 0.05). This vitamin B-12-deficient diet, which was of insufficient severity to cause anemia or illness, created aberrations in both base substitution and methylation of colonic DNA, which might increase susceptibility to carcinogenesis.

Topics: Animals; Body Weight; Colon; Colorectal Neoplasms; DNA; DNA Methylation; Epithelium; Folic Acid; Gas Chromatography-Mass Spectrometry; Intestinal Mucosa; Male; Rats; Rats, Sprague-Dawley; Uracil; Vitamin B 12; Vitamin B 12 Deficiency

Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects.. The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 +/- 0.6 ng/mL) compared with wild-types (8.8 +/- 0.4 ng/mL) and heterozygotes (9.1 +/- 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 +/- 1.1 micromol/L) compared with homozygous subjects (10.9 +/- 0.4 micromol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 +/- 6.3 ng/mL) compared with wild-types (112.2 +/- 5.2 ng/mL) and heterozygous individuals (125.1 +/- 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants.. Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; DNA Damage; DNA Methylation; Erythrocytes; Female; Folic Acid; Genetic Carrier Screening; Genetic Variation; Genotype; Homocysteine; Homozygote; Humans; Isoenzymes; Lymphocytes; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Genetic; Risk; Scotland; Tetrahydrofolates; Uracil; Vitamin B 12

Topics: Adenomatous Polyps; Case-Control Studies; Colorectal Neoplasms; DNA; DNA Methylation; Folic Acid; Gene Expression Regulation, Neoplastic; Genotype; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Oligonucleotide Array Sequence Analysis; Oxidoreductases Acting on CH-NH Group Donors; Research Design; Risk Factors; Tumor Cells, Cultured; Vitamin B 12

It is hypothesized that diets deficient in folate, methionine, and vitamins B-6 and B-12 cause DNA hypomethylation and, as a result, increase risk of colorectal cancers. Furthermore, it is proposed that alcohol, a methyl group antagonist, increases risk of colorectal cancers among those with low intake of folate. Data from the Iowa Women's Health Study, a population-based cohort of incident cancer, were used to examine the relationship of folate, methionine, and vitamins B-6 and B-12 to occurrence of cancers of the colon (n = 598) and rectum (n = 123) over 13 yr of follow-up. There were no independent associations of folate, methionine, or vitamins B-6 and B-12 derived from a food frequency questionnaire with incidence of colon cancer. Adjusted relative risks (RRs) of rectal cancer were similar across categories of folate, vitamin B-12, and methionine intake, but RRs increased progressively with increasing intake of vitamin B-6 [P (for trend) = 0.03]. RRs suggested that incidence of cancer of the proximal colon was lower among those with 1) high folate and high vitamin B-12 intake [RR = 0.59, 95% confidence interval (CI) = 0.39-0.89] and 2) high folate and high vitamin B-6 intake (RR = 0.65, 95% CI = 0.50-0.84) than among those with the lowest intake of these nutrients. Incidence of cancer of the proximal colon was also somewhat lower among those with high folate and low alcohol intake (RR = 0.44, 95% CI = 0.22-0.89). Findings provide limited support for an association between dietary factors involved in DNA methylation and risk of cancers of the colon and rectum.

Topics: Aged; Alcohol Drinking; Cohort Studies; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Humans; Incidence; Iowa; Methionine; Middle Aged; Risk Factors; Surveys and Questionnaires; Vitamin B 12; Vitamin B 6

We previously reported (J. Chen et al., Cancer Res., 56: 4862-4864, 1996; J. Ma et al., Cancer Res., 57: 1098-1102, 1997) that a 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism (677C-->T, ala-->val) was associated with lower risk of colorectal cancer. In this study, we examined the relationship of a polymorphism (2756A-->G, asp-->gly) in the gene (MTR) for methionine synthase, another important enzyme in the same folate/methionine/homocyst(e)ine metabolic pathway, with risk of colorectal cancer among 356 cases and 476 cancer-free controls. The frequency of the homozygous variant genotype (gly/gly) was slightly lower among cases (3%) than controls (5%). The odds ratio for the gly/gly genotype was 0.59 [95% confidence interval (CI), 0.27-1.27] compared with those with the homozygous wild type (asp/asp). There were no significant differences in plasma levels of folate, vitamin B12, and homocyst(e)ine (tHcy) among the MTR genotypes, in contrast to the MTHFR polymorphism. However, similar to the interaction observed for the MTHFR polymorphism among men who consumed less than 1 alcoholic drink/day, those with the gly/gly genotype had a lower risk of colorectal cancer with an odds ratio of 0.27 (95% CI, 0.09-0.81) compared with those with the asp/asp genotype. The possible association of the MTR polymorphism with lower risk of colorectal cancer especially among those with low alcohol consumption, in the same direction as for the MTHFR polymorphism, is intriguing. However, our study had limited statistical power because of the low frequency of the MTR variant genotype, which is reflected in the wide CIs. Hence, these findings need to be confirmed in larger populations.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adult; Aged; Aged, 80 and over; Alcohol Drinking; Canada; Case-Control Studies; Colorectal Neoplasms; Folic Acid; Genotype; Homocysteine; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Risk Factors; Surveys and Questionnaires; United States; Vitamin B 12; White People