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Franco CN, Seabrook LJ, Nguyen ST, Yang Y, Campos M, Fan Q, Cicchetto AC, Kong M, Christofk HR, Albrecht LV. Vitamin B 6 is governed by the local compartmentalization of metabolic enzymes during growth. SCIENCE ADVANCES 2023; 9:eadi2232. [PMID: 37682999 PMCID: PMC10491294 DOI: 10.1126/sciadv.adi2232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/08/2023] [Indexed: 09/10/2023]
Abstract
Vitamin B6 is a vital micronutrient across cell types and tissues, and dysregulated B6 levels contribute to human disease. Despite its importance, how B6 vitamer levels are regulated is not well understood. Here, we provide evidence that B6 dynamics are rapidly tuned by precise compartmentation of pyridoxal kinase (PDXK), the rate-limiting B6 enzyme. We show that canonical Wnt rapidly led to the accumulation of inactive B6 by shunting cytosolic PDXK into lysosomes. PDXK was modified with methyl-arginine Degron (MrDegron), a protein tag for lysosomes, which enabled delivery via microautophagy. Hyperactive lysosomes resulted in the continuous degradation of PDXK and B6 deficiency that promoted proliferation in Wnt-driven colorectal cancer (CRC) cells. Pharmacological or genetic disruption of the coordinated MrDegron proteolytic pathway was sufficient to reduce CRC survival in cells and organoid models. In sum, this work contributes to the repertoire of micronutrient-regulated processes that enable cancer cell growth and provides insight into the functional impact of B6 deficiencies for survival.
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Affiliation(s)
- Carolina N. Franco
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Laurence J. Seabrook
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Steven T. Nguyen
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
| | - Ying Yang
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Melissa Campos
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
| | - Qi Fan
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Andrew C. Cicchetto
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mei Kong
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Heather R. Christofk
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lauren V. Albrecht
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, Irvine, CA, USA
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Lai J, Guo M, Wang D, Liu K, Hu D, Li J. Association Between Vitamin B6 and the Risk of Colorectal Cancer: A Meta-analysis of Observational Studies. Nutr Cancer 2023; 75:1281-1294. [PMID: 36961108 DOI: 10.1080/01635581.2023.2191823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/07/2023] [Accepted: 03/12/2023] [Indexed: 03/25/2023]
Abstract
OBJECTIVE This meta-analysis aimed to assess the association between vitamin B6 intake, blood PLP levels, and the risk of colorectal cancer. METHODS 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. RESULTS 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)]. CONCLUSION In this meta-analysis, vitamin B6 intake and blood PLP levels were inversely associated with colorectal cancer risk.
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Affiliation(s)
- Jianxiong Lai
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Mingqiao Guo
- Department of General Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Dongmei Wang
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Kuan Liu
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Dengmin Hu
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, China
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Fu H, He J, Li C, Deng Z, Chang H. Folate intake and risk of colorectal cancer: a systematic review and up-to-date meta-analysis of prospective studies. Eur J Cancer Prev 2023; 32:103-112. [PMID: 35579178 DOI: 10.1097/cej.0000000000000744] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE Colorectal cancer is one of the most commonly diagnosed and deadly cancers worldwide. Epidemiological studies on the relationship between folate intake and the risk of colorectal cancer have reported inconsistent findings since folate fortification in the USA. For this situation, we conducted a large number of data analyses to study the relationship between folate intake and colorectal cancer risk. METHODS PubMed and EMBASE databases were used to search the literature systematically. Eligible studies were reviewed and meta-analyzed to assess the relationship. RESULTS A total of 24 cohort studies involving 37 280 patients and 6 165 894 individuals were included. The results showed that high folate intake was associated with a reduced risk of colorectal cancer. The combined relative risk (RR) for the highest intake compared with the lowest was 0.88 [95% confidence interval (CI), 0.83-0.92, P = 10 -4 ). Further studies indicated that the increase of folate intake may decrease the risk of colorectal cancer in people with medium or high alcohol consumption (RR = 0.97, 95% CI: 0.96-0.99, P = 0.008; RR = 0.95, 95% CI: 0.92-0.98, P = 0.003), but not in non-drinkers (RR = 1.00, 95% CI: 0.98-1.02, P = 0.827). Next, high folate intake may decrease the risk of colon cancer (RR = 0.86, 95% CI: 0.81-0.92, P = 10 -4 ) but not rectal cancer (RR = 0.92, 95% CI: 0.84-1.02, P = 0.112). Additionally, the result that high folate intake may decrease the risk of colorectal cancer was observed in the USA and Europe but not in other regions. CONCLUSION High folate intake may be protective against colon cancer, particularly in people with middle or high alcohol consumption, but it still needs to be further confirmed.
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Affiliation(s)
- Hongjuan Fu
- College of Food Science, Southwest University, Chongqing, China
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Chávez-Hidalgo LP, Martín-Fernández-de-Labastida S, M de Pancorbo M, Arroyo-Izaga M. Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies. World J Gastroenterol 2023; 29:1219-1234. [PMID: 36926668 PMCID: PMC10011952 DOI: 10.3748/wjg.v29.i7.1219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/26/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). However, whether the influence of methyl donor intake is modified by polymorphisms in such epigenetic regulators is still unclear.
AIM To improve the current understanding of the molecular basis of CRC.
METHODS A literature search in the Medline database, Reference Citation Analysis (https://www.referencecitationanalysis.com/), and manual reference screening were performed to identify observational studies published from inception to May 2022.
RESULTS A total of fourteen case-control studies and five cohort studies were identified. These studies included information on dietary methyl donors, dietary components that potentially modulate the bioavailability of methyl groups, genetic variants of methyl metabolizing enzymes, and/or markers of CpG island methylator phenotype and/or microsatellite instability, and their possible interactions on CRC risk.
CONCLUSION Several studies have suggested interactions between methylenetetrahydrofolate reductase polymorphisms, methyl donor nutrients (such as folate) and alcohol on CRC risk. Moreover, vitamin B6, niacin, and alcohol may affect CRC risk through not only genetic but also epigenetic regulation. Identification of specific mechanisms in these interactions associated with CRC may assist in developing targeted prevention strategies for individuals at the highest risk of developing CRC.
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Affiliation(s)
- Lourdes Pilar Chávez-Hidalgo
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Silvia Martín-Fernández-de-Labastida
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Marian M de Pancorbo
- Department of Z. and Cellular Biology A., University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
- BIOMICs Research Group, MICROFLUIDICs and BIOMICs Cluster UPV/EHU, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
| | - Marta Arroyo-Izaga
- Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
- BIOMICs Research Group, MICROFLUIDICs and BIOMICs Cluster UPV/EHU, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
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5
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Noreldeen HAA, Huang KY, Wu GW, Peng HP, Deng HH, Chen W. Deep Learning-Based Sensor Array: 3D Fluorescence Spectra of Gold Nanoclusters for Qualitative and Quantitative Analysis of Vitamin B 6 Derivatives. Anal Chem 2022; 94:9287-9296. [PMID: 35723526 DOI: 10.1021/acs.analchem.2c00655] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Vitamin B6 derivatives (VB6Ds) are of great importance for all living organisms to complete their physiological processes. However, their excess in the body can cause serious problems. What is more, the qualitative and quantitative analysis of different VB6Ds may present significant challenges due to the high similarity of their chemical structures. Also, the transfer of deep learning model from one task to a similar task needs to be present more in the fluorescence-based biosensor. Therefore, to address these problems, two deep learning models based on the intrinsic fingerprint of 3D fluorescence spectra have been developed to identify five VB6Ds. The accuracy ranges of a deep neural network (DNN) and a convolutional neural network (CNN) were 94.44-97.77% and 97.77-100%, respectively. After that, the developed models were transferred for quantitative analysis of the selected VB6Ds at a broad concentration range (1-100 μM). The determination coefficient (R2) values of the test set for DNN and CNN were 93.28 and 97.01%, respectively, which also represents the outperformance of CNN over DNN. Therefore, our approach opens new avenues for qualitative and quantitative sensing of small molecules, which will enrich fields related to deep learning, analytical chemistry, and especially sensor array chemistry.
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Affiliation(s)
- Hamada A A Noreldeen
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.,National Institute of Oceanography and Fisheries, NIOF, Cairo 4262110, Egypt
| | - Kai-Yuan Huang
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350004, China
| | - Gang-Wei Wu
- Department of Pharmacy, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Hua-Ping Peng
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350004, China
| | - Hao-Hua Deng
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350004, China
| | - Wei Chen
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, School of Pharmacy, Fujian Medical University, Fuzhou 350004, China
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Holowatyj AN, Ose J, Gigic B, Lin T, Ulvik A, Geijsen AJMR, Brezina S, Kiblawi R, van Roekel EH, Baierl A, Böhm J, Bours MJL, Brenner H, Breukink SO, Chang-Claude J, de Wilt JHW, Grady WM, Grünberger T, Gumpenberger T, Herpel E, Hoffmeister M, Keulen ETP, Kok DE, Koole JL, Kosma K, Kouwenhoven EA, Kvalheim G, Li CI, Schirmacher P, Schrotz-King P, Singer MC, van Duijnhoven FJB, van Halteren HK, Vickers K, Vogelaar FJ, Warby CA, Wesselink E, Ueland PM, Ulrich AB, Schneider M, Habermann N, Kampman E, Weijenberg MP, Gsur A, Ulrich CM. Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer. Am J Clin Nutr 2022; 116:303-313. [PMID: 35394006 PMCID: PMC9348990 DOI: 10.1093/ajcn/nqac090] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 04/04/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. OBJECTIVES We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. METHODS A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. RESULTS After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). CONCLUSION Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.
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Affiliation(s)
- Andreana N Holowatyj
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA,Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jennifer Ose
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Biljana Gigic
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Tengda Lin
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | | | - Anne J M R Geijsen
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Stefanie Brezina
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
| | - Rama Kiblawi
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA,Medical Faculty, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
| | - Eline H van Roekel
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Andreas Baierl
- Department of Statistics and Operations Research, University of Vienna, Austria
| | - Jürgen Böhm
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Martijn J L Bours
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Hermann Brenner
- Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stéphanie O Breukink
- Department of Surgery, GROW School for Oncology and Development Biology, Maastricht University, The Netherlands
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg Germany
| | - Johannes H W de Wilt
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Radboud University Medical Center, The Netherlands
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - Tanja Gumpenberger
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
| | - Esther Herpel
- Institute of Pathology, University of Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Eric T P Keulen
- Department of Internal Medicine and Gastroenterology, Zuyderland Medical Center, Sittard, The Netherlands
| | - Dieuwertje E Kok
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Janna L Koole
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Katharina Kosma
- Department of Surgery, Kaiser Franz Josef Hospital, Vienna, Austria
| | | | | | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | - Petra Schrotz-King
- Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany
| | - Marie C Singer
- Department of Surgery, Kaiser Franz Josef Hospital, Vienna, Austria
| | | | - Henk K van Halteren
- Department of Internal Medicine, Admiraal de Ruyter Hospital, Goes, The Netherlands
| | - Kathy Vickers
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - F Jeroen Vogelaar
- Department of Surgery, VieCuri Medical Center, Venlo, The Netherlands
| | - Christy A Warby
- Huntsman Cancer Institute, Salt Lake City, Utah, USA,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | | | - Alexis B Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Martin Schneider
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany
| | - Nina Habermann
- Genome Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Ellen Kampman
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria
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Dietary B vitamin and methionine intakes and risk for colorectal cancer: a case-control study in China. Br J Nutr 2020; 123:1277-1289. [PMID: 32054547 DOI: 10.1017/s0007114520000501] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
B vitamins (including folate, vitamin B2, vitamin B6 and vitamin B12) and methionine are essential for methylation reactions, nucleotide synthesis, DNA stability and DNA repair. However, epidemiological evidence among Chinese populations is limited. The objective of this study was to evaluate B vitamins and methionine in relation to colorectal cancer risk in a Chinese population. A case-control study was conducted from July 2010 to April 2019. A total of 2502 patients with colorectal cancer were recruited along with 2538 age- (5-year interval) and sex-matched controls. Dietary data were collected using a validated FFQ. Multivariable logistic regression was used to assess OR and 95 % CI. The intake of folate, vitamin B2, vitamin B6 and vitamin B12 was inversely associated with colorectal cancer risk. The multivariable OR for the highest quartile v. the lowest quartile were 0·62 (95 % CI 0·51, 0·74; Ptrend < 0·001) for folate, 0·46 (95 % CI 0·38, 0·55; Ptrend < 0·001) for vitamin B2, 0·55 (95 % CI 0·46, 0·76; Ptrend < 0·001) for vitamin B6 and 0·72 (95 % CI 0·60, 0·86; Ptrend < 0·001) for vitamin B12. No statistically significant association was found between methionine intake and colorectal cancer risk. Stratified analysis by sex showed that the inverse associations between vitamin B12 and methionine intake and colorectal cancer risk were found only among women. This study indicated that higher intake of folate, vitamin B2, vitamin B6 and vitamin B12 was associated with decreased risk of colorectal cancer in a Chinese population.
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8
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Cruciferous vegetable intake and colorectal cancer risk: Japan public health center-based prospective study. Eur J Cancer Prev 2018; 28:420-427. [PMID: 30399043 DOI: 10.1097/cej.0000000000000491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We aimed to assess the association between cruciferous vegetable intake and colorectal cancer (CRC) development among Japanese adults aged between 45 and 74 years in the Japan Public Health Center-based Prospective Study. During 1 325 853 person-years of follow-up, 2612 CRC cases were identified. The association of cruciferous vegetable intake with CRC risk was assessed using a Cox proportional hazard regression model to compute hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. No significant association was observed between the highest cruciferous vegetable intake quartile (compared with the lowest) and CRC risk in men (multivariate HRs: 1.08; 95% CI: 0.91, 1.29) and women (multivariate HRs: 0.99; 95% CI: 0.80, 1.22) and its subsites. Women showed a marginal negative association between cruciferous vegetable intake and the risk of colon cancer (CC) after excluding participants who developed CC in the first 3 years of follow-up (P for trend = 0.08); a positive association was found with proximal CC in men. Cruciferous vegetable intake does not have a significant association with CRC risk in the Japanese general population.
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9
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Matsuo T, Fujiwara A, Nakamura K, Sadzuka Y. The effects of vitamin B 6 compounds on cell proliferation and melanogenesis in B16F10 melanoma cells. Oncol Lett 2018; 15:5181-5184. [PMID: 29552155 DOI: 10.3892/ol.2018.7947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/23/2018] [Indexed: 11/05/2022] Open
Abstract
B16F10 murine melanoma cells are frequently used for the study of cancer and melanogenesis. The cells are usually cultured in Dulbecco's Modified Eagle Medium, with the addition of 20 µM pyridoxal (PL) or pyridoxine (PN) for vitamin B6. The difference between these vitamin B6 compounds is thought not to affect cell proliferation, whereas their influence on other physiological effects is poorly understood. In the present study, the effects of PL and PN on cell proliferation and melanogenesis in B16F10 cells were compared. At 500 µM PL significantly suppressed cell growth but the growth inhibitory effect of PN was weak. Although neither of the vitamin B6 compounds affected cell growth at 20 µM, melanogenesis was suppressed by 20 µM PL compared with the effect of PN. In addition, the expression levels of tyrosinase, which is the rate-limiting enzyme, correlated with the melanin content. The results of the present study indicate that PL may be more useful for melanoma therapy and suppression of skin pigmentation than PN. The results also signify the importance of medium selection for cell culture.
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Affiliation(s)
- Taisuke Matsuo
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan
| | - Aki Fujiwara
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan
| | - Kazuhiro Nakamura
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan
| | - Yasuyuki Sadzuka
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan
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10
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Jia K, Wang R, Tian J. Vitamin B6Intake and the Risk of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies. Nutr Cancer 2017; 69:723-731. [PMID: 28569561 DOI: 10.1080/01635581.2017.1324633] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Kai Jia
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Rong Wang
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jingfeng Tian
- Department of Nutrition, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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11
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Zhang D, Wen X, Wu W, Guo Y, Cui W. Elevated homocysteine level and folate deficiency associated with increased overall risk of carcinogenesis: meta-analysis of 83 case-control studies involving 35,758 individuals. PLoS One 2015; 10:e0123423. [PMID: 25985325 PMCID: PMC4436268 DOI: 10.1371/journal.pone.0123423] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 02/24/2015] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. METHOD Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. RESULTS We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. CONCLUSION Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer.
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Affiliation(s)
- Donghong Zhang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xuemei Wen
- Department of Clinical Laboratory, Fudan University Cancer Center, Shanghai, China
| | - Wei Wu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ye Guo
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Morita M, Yin G, Yoshimitsu SI, Ohnaka K, Toyomura K, Kono S, Ueki T, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Maekawa T, Yasunami Y, Takenaka K, Ichimiya H, Terasaka R. Folate-related nutrients, genetic polymorphisms, and colorectal cancer risk: the fukuoka colorectal cancer study. Asian Pac J Cancer Prev 2015; 14:6249-56. [PMID: 24377513 DOI: 10.7314/apjcp.2013.14.11.6249] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.
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Affiliation(s)
- Makiko Morita
- Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan E-mail :
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13
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Liu Y, Yu Q, Zhu Z, Zhang J, Chen M, Tang P, Li K. Vitamin and multiple-vitamin supplement intake and incidence of colorectal cancer: a meta-analysis of cohort studies. Med Oncol 2015; 32:434. [PMID: 25491145 DOI: 10.1007/s12032-014-0434-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023]
Abstract
This paper systematically evaluated the association of intake of different vitamins and multiple-vitamin supplements and the incidence of colorectal cancer. Relevant studies were identified in MEDLINE via PubMed (published up to April 2014). We extracted data from articles on vitamins A, C, D, E, B9 (folate), B2, B3, B6, and B12 and multiple-vitamin supplements. We used multivariable-adjusted relative risks (RRs) and a random-effects model for analysis and random effects. With heterogeneity, we looked for the source of heterogeneity or performed sensitivity and stratified analyses. We found 47 articles meeting the inclusion criteria. The multivariable-adjusted RR for pooled studies for the association between the highest versus lowest vitamin B9 (folate) intake and colorectal cancer was 0.88 [95 % confidence interval (95 % CI) 0.81-0.95]. Vitamin D was 0.87 (95 % CI 0.77-0.99); vitamin B6, 0.88 (95 % CI 0.79-0.99); vitamin B2, 0.86 (95 % CI, 0.76-0.97); vitamin A, 0.87 (95 % CI, 0.75-1.03); vitamin C, 0.92 (95 % CI, 0.80-1.06); vitamin E, 0.94 (95 % CI, 0.82-1.07); vitamin B12, 1.10 (95 % CI, 0.92-1.32); vitamin B3, 1.18 (95 % CI, 0.76-1.84). Vitamin B9 (folate), D, B6, and B2 intake was inversely associated with risk of colorectal cancer, but further study is needed. Our study featured unacceptable heterogeneity for studies of multiple-vitamin supplements, so findings were inconclusive.
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Affiliation(s)
- Yan Liu
- Department of Public Health, Shantou University Medical College, No. 22 Xinling Road, Shantou, 515041, Guangdong, China,
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14
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Zhang P, Suidasari S, Hasegawa T, Yanaka N, Kato N. Vitamin B₆ activates p53 and elevates p21 gene expression in cancer cells and the mouse colon. Oncol Rep 2014; 31:2371-6. [PMID: 24626782 DOI: 10.3892/or.2014.3073] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 02/10/2014] [Indexed: 11/06/2022] Open
Abstract
Increasing evidence indicates vitamin B6 acts as a protective factor against colon cancer. However, the mechanisms of the effect of vitamin B6 are poorly understood. The present preliminary study using DNA microarray and real-time PCR indicates p21 mRNA is upregulated in human colon carcinoma (HT29) cells exposed to pyridoxal (PL, 500 µM). A similar effect was observed in human epithelial colorectal adenocarcinoma (Caco2) cells, human colon adenocarcinoma (LoVo) cells, human embryonic kidney (HEK293T) cells, and human hepatoma (HepG2) cells. Adding other B6-vitamers such as pyridoxal 5'-phosphate (PLP), pyridoxine (PN), and pyridoxamine (PM) caused no such effect. In order to understand the mechanism of higher mRNA expression of p21 by PL, effect of PL on the p53 activation was examined (the upstream factor for p21 mRNA transcription) in HT29 cells, LoVo cells, and HepG2 cells. PL increased the phosphorylated p53 protein levels (active form) in whole-cell lysates and the nuclei of the cells. Noteworthy, the consumption of a vitamin B6-deficient diet for 5 weeks significantly reduced p21 mRNA levels and tended to reduce phosphorylated p53 protein levels (P=0.053) in the colons of mice compared to a diet with adequate vitamin B6. Thus, these results suggest vitamin B6 plays a role in increasing p21 gene expression via p53 activation in several cancer cells and the mouse colon.
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Affiliation(s)
- Peipei Zhang
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Sofya Suidasari
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Tomomi Hasegawa
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Noriyuki Yanaka
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Norihisa Kato
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
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15
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Zhou ZY, Wan XY, Cao JW. Dietary methionine intake and risk of incident colorectal cancer: a meta-analysis of 8 prospective studies involving 431,029 participants. PLoS One 2013; 8:e83588. [PMID: 24340103 PMCID: PMC3858442 DOI: 10.1371/journal.pone.0083588] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Accepted: 11/14/2013] [Indexed: 12/21/2022] Open
Abstract
Background Methionine is one of the key components of one carbon metabolism. Experimental studies indicate that methionine may reduce inflammation-induced colon cancer. However, epidemiologic findings as to whether dietary methionine intake influences colorectal cancer incidence in humans are inconsistent. Objective To investigate the relationship between dietary methionine intake and risk of colorectal cancer by performing a meta-analysis of prospective studies. Methods Eligible studies were identified by searching PubMed and Embase and by reviewing the bibliographies of the retrieved publications. The summary risk estimates were computed using both a random- effects and a fixed-effects model. Results Eight eligible prospective cohort studies involving 431,029 participants and 6,331 colorectal cancer cases were identified. According to the random-effects model, the summary relative risks (RRs) for the highest compared with the lowest intake of methionine were 0.89 (95% confidence interval [CI] = 0.77-1.03) for colorectal cancer, 0.77 (95% CI = 0.64 - 0.92) for colon cancer, and 0.88 (95% CI = 0.55-1.42) for rectal cancer. In the stratified analysis, a significant inverse association between dietary methionine intake and risk of colorectal cancer was observed in studies with longer follow-up time (RR=0.81, 95% CI= 0.70- 0.95), in Western studies (RR= 0.83, 95% CI = 0.73 - 0.95) and in men (RR = 0.75, 95% CI= 0.57-0.99). We found no indication of publication bias. Conclusion This meta-analysis indicates that dietary methionine intake may be associated with decreased risk of colorectal cancer, especially colon cancer. More prospective studies with long follow-up time are needed to confirm these findings.
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Affiliation(s)
- Zhong-Yin Zhou
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- * E-mail:
| | - Xin-Yue Wan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Ji-Wang Cao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Zhang P, Suidasari S, Hasegawa T, Yanaka N, Kato N. High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c‑Jun pathway. Mol Med Rep 2013; 8:973-8. [PMID: 23942851 DOI: 10.3892/mmr.2013.1629] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 08/08/2013] [Indexed: 11/05/2022] Open
Abstract
Increasing evidence suggests that dietary vitamin B6 is linked to the prevention of cancer and cardiovascular disease. However, the molecular mechanisms involved in this process are not yet understood. Preliminary results in the current study indicated, following DNA microarray analysis and quantitative PCR, that insulin‑like growth factor‑binding protein 1 (IGFBP1) mRNA is upregulated in HT29 colon carcinoma cells exposed to pyridoxal (PL, 500 µM). IGFBP1 is secreted from the liver and is hypothesized to exert a protective role in the development of cancer and cardiovascular disease. Thus, further experiments were performed to investigate the effect of PL on the expression of IGFBP1 in HepG2 hepatocellular carcinoma cells. The addition of PL (500 µM) markedly increased the expression of IGFBP1 mRNA in HepG2 cells at 6, 12 and 24 h (P<0.01), whereas other vitamers (500 µM), including pyridoxal 5'‑phosphate (PLP), pyridoxine (PN) and pyridoxamine (PM), caused no such effect. The expression of the IGFBP1 protein in the cell lysate and culture medium was elevated in the presence of PL. PL elevated expression of the active form of ERK1 protein, p‑ERK1, and the p‑c‑Jun protein, a downstream factor of ERK. Furthermore, IGFBP1 expression, elevated by PL, was suppressed by PD98059, an ERK inhibitor. Higher expression of IGFBP1 protein by PL was suppressed by cycloheximide. These results suggest that PL may induce the expression of IGFBP1 in hepatoma cells via a mechanism involving the ERK/c‑Jun pathway.
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Affiliation(s)
- Peipei Zhang
- Graduate School of Biosphere Science, Hiroshima University, Higashi‑Hiroshima, Hiroshima 739‑8528, Japan
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Ashmore JH, Lesko SM, Muscat JE, Gallagher CJ, Berg AS, Miller PE, Hartman TJ, Lazarus P. Association of dietary and supplemental folate intake and polymorphisms in three FOCM pathway genes with colorectal cancer in a population-based case-control study. Genes Chromosomes Cancer 2013; 52:945-53. [PMID: 23893618 DOI: 10.1002/gcc.22089] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 06/17/2013] [Accepted: 06/18/2013] [Indexed: 12/18/2022] Open
Abstract
Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC.
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Affiliation(s)
- Joseph H Ashmore
- Department of Nutritional Sciences, Pennsylvania State University, College of Health and Human Development, State College, PA, USA
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18
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Okazaki Y, Utama Z, Suidasari S, Zhang P, Yanaka N, Tomotake H, Sakaguchi E, Kato N. Consumption of vitamin B(6) reduces fecal ratio of lithocholic acid to deoxycholic acid, a risk factor for colon cancer, in rats fed a high-fat diet. J Nutr Sci Vitaminol (Tokyo) 2013; 58:366-70. [PMID: 23327973 DOI: 10.3177/jnsv.58.366] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
To examine the effect of supplemental dietary vitamin B(6) on the colonic luminal environment, growing male rats were fed a high-fat diet containing 1, 7, or 35 mg pyridoxine HCl/kg diet for 6 wk. Food intake and growth were unaffected by the dietary treatment. Supplemental dietary vitamin B(6) significantly reduced the production of a fecal secondary bile acid, lithocholic acid (the most toxic secondary bile acid and a risk factor for colon cancer), and markedly reduced the ratio of lithocholic acid to deoxycholic acid (a less toxic secondary bile acid) in feces (p<0.05). Increasing dietary vitamin B(6) increased fecal mucin levels (a marker of intestinal barrier function) in a dose-dependent manner (p<0.05) but did not affect fecal immunoglobulin A levels (an index of intestinal immune function). Cecal levels of organic acids were not significantly affected by supplemental dietary vitamin B(6). These results suggest the possibility that dietary vitamin B(6) affects the colonic luminal environment by altering the production of secondary bile acids and mucins.
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Affiliation(s)
- Yukako Okazaki
- Faculty of Human Life Sciences, Fuji Women's University, Ishikari, Japan.
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Bassett JK, Severi G, Hodge AM, Baglietto L, Hopper JL, English DR, Giles GG. Dietary Intake of B Vitamins and Methionine and Colorectal Cancer Risk. Nutr Cancer 2013; 65:659-67. [DOI: 10.1080/01635581.2013.789114] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Kuwahara K, Nanri A, Pham NM, Kurotani K, Kume A, Sato M, Kawai K, Kasai H, Mizoue T. Serum vitamin B6, folate, and homocysteine concentrations and oxidative DNA damage in Japanese men and women. Nutrition 2013; 29:1219-23. [PMID: 23800563 DOI: 10.1016/j.nut.2013.03.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 03/08/2013] [Accepted: 03/12/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Higher vitamin B status has been linked to a lower risk for cancer, but the underlying mechanism remains elusive. The aim of the present study was to examine the association of pyridoxal, folate, and homocysteine (Hcy) with urinary 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage. METHODS The participants were 500 employees (293 men and 207 women), ages 21 to 66 y, of two municipal offices in Japan. Serum pyridoxal and Hcy concentrations were measured using high-performance liquid chromatography (HPLC) method, and serum folate concentrations were measured using chemiluminescent immunoassay. Urinary 8-OHdG concentrations were measured using HPLC method. Multiple regression was used to estimate means of 8-OHdG for each tertile of pyridoxal, folate, and Hcy with adjustment for potential confounders. RESULTS In multivariate analysis, 8-OHdG concentration was inversely associated with pyridoxal concentration in men (P for trend = 0.045) but not in women. The association in men was confined to non-smokers (P for trend = 0.033) or those who consumed no or < 20 g/d of ethanol (P for trend = 0.048). 8-OHdG concentrations were not appreciably associated with folate and Hcy concentrations. CONCLUSION The results suggest that vitamin B6, but not folate and homocysteine, plays a role against oxidative DNA damage in Japanese men.
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Affiliation(s)
- Keisuke Kuwahara
- Department of Epidemiology and Prevention, Clinical Research Center, National Center for Global Health and Medicine, Tokyo, Japan.
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21
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Zschäbitz S, Cheng TYD, Neuhouser ML, Zheng Y, Ray RM, Miller JW, Song X, Maneval DR, Beresford SAA, Lane D, Shikany JM, Ulrich CM. B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort. Am J Clin Nutr 2013; 97:332-43. [PMID: 23255571 PMCID: PMC3545682 DOI: 10.3945/ajcn.112.034736] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 10/23/2012] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake. OBJECTIVE We investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Women's Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake. DESIGN A total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models. RESULTS Dietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01). CONCLUSIONS Vitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk.
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Affiliation(s)
- Stefanie Zschäbitz
- Division of Preventive Oncology, National Center for Tumor Diseases, Heidelberg, Germany
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22
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Galluzzi L, Vacchelli E, Michels J, Garcia P, Kepp O, Senovilla L, Vitale I, Kroemer G. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene 2013; 32:4995-5004. [PMID: 23334322 DOI: 10.1038/onc.2012.623] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2012] [Revised: 11/21/2012] [Accepted: 11/26/2012] [Indexed: 12/17/2022]
Abstract
Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.
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Affiliation(s)
- L Galluzzi
- 1] Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France [2] Institut Gustave Roussy, Villejuif, France
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Zhang X, Lee JE, Ma J, Je Y, Wu K, Willett WC, Fuchs CS, Giovannucci EL. Prospective cohort studies of vitamin B-6 intake and colorectal cancer incidence: modification by time? Am J Clin Nutr 2012; 96:874-81. [PMID: 22875713 PMCID: PMC3441113 DOI: 10.3945/ajcn.112.037267] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The relation between vitamin B-6 intake and colorectal cancer risk remains uncertain. OBJECTIVE We prospectively evaluated whether a higher vitamin B-6 intake in the remote past is more strongly associated with a lower risk of colorectal cancer than is an intake in the recent past in the Nurses' Health Study and the Health Professionals Follow-Up Study. DESIGN We assessed vitamin B-6 intake every 4 y by using validated food-frequency questionnaires and followed 86,440 women and 44,410 men for ≤28 y. Cox proportional hazards regression was used to estimate multivariable RRs and 95% CIs. RESULTS The total vitamin B-6 intake was significantly associated with an ∼20-30% lower risk of colorectal cancer in age-adjusted results, but this association became attenuated and nonsignificant after additional adjustment for nondietary and dietary factors. When the highest to lowest quintiles of cumulative total vitamin B-6 intake were compared, RRs (95% CIs) for colorectal cancer were 0.99 (0.80, 1.24; P-trend = 0.55) for women and 0.95 (0.73, 1.23; P-trend = 0.75) for men. For the same comparison, RRs were 0.92 (0.73, 1.16) for total vitamin B-6 intake 0-4 y before diagnosis, 0.99 (0.78, 1.26) for intake 4-8 y before diagnosis, 0.92 (0.71, 1.21) for intake 8-12 y before diagnosis, and 0.93 (0.69, 1.26) for intake 12-16 y before diagnosis in women. Corresponding RRs for men were 0.86 (0.63, 1.17), 0.96 (0.70, 1.32), 0.90 (0.63, 1.29), and 1.16 (0.75, 1.79). Results did not differ by cancer subsite, source of vitamin B-6 (food or supplement), alcohol consumption, or folate intake. CONCLUSION Our data do not support a strong role of adulthood vitamin B-6 intake in colorectal carcinogenesis in these US health professionals.
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Affiliation(s)
- Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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Hara A, Sasazuki S, Inoue M, Iwasaki M, Shimazu T, Sawada N, Yamaji T, Takachi R, Tsugane S. Zinc and heme iron intakes and risk of colorectal cancer: a population-based prospective cohort study in Japan. Am J Clin Nutr 2012; 96:864-73. [PMID: 22952177 DOI: 10.3945/ajcn.112.041202] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND 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. OBJECTIVE We investigated the association between zinc and heme iron intakes and colorectal cancer risk in a Japanese general population. DESIGN 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. RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Azusa Hara
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
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Kayashima T, Tanaka K, Okazaki Y, Matsubara K, Yanaka N, Kato N. Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine. Oncol Lett 2011; 2:1243-1246. [PMID: 22848295 DOI: 10.3892/ol.2011.370] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Accepted: 07/15/2011] [Indexed: 12/31/2022] Open
Abstract
Mounting evidence indicates that vitamin B6 is a protective factor for colon cancer. Elevations in colonic damage, cell proliferation and heat shock proteins (HSPs, molecular chaperones) have been suggested to be associated with colon carcinogenesis. This study was performed to examine the effect of dietary levels of vitamin B6 (1, 7 or 35 mg pyridoxine HCl/kg diet) for 22 weeks on colon damage, epithelial cell proliferation and expression of HSPs in rats exposed to 1,2-dimethylhydrazine (DMH). Supplemental vitamin B6 with a low vitamin B6 diet (1 mg pyridoxine HCl/kg diet) significantly reduced fecal activity of intestinal alkaline phosphatase (an index of intestinal damage) and the colonic epithelium PCNA labeling index (a marker of cell proliferation). Analysis using ELISA indicated that supplemental vitamin B6 significantly lowered protein levels of colonic HSP70 and heme oxygenase-1, HSP32 (HO-1). However, real-time RT-PCR analysis revealed that the mRNA levels of these HSPs were not decreased by supplemental vitamin B6, suggesting that the lowering effect of vitamin B6 on the colon protein expression of the HSPs is mediated by mechanisms not involving altered gene expression. This study provided evidence that dietary supplemental vitamin B6 suppresses colon damage, epithelial cell proliferation and protein expression of HSP70 and HO-1, the targets for anti-tumor agents, in rats exposed to DMH.
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Affiliation(s)
- Tomoko Kayashima
- Graduate School of Education, Hiroshima University, Higashi-Hiroshima 739-8524
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Stevens VL, McCullough ML, Sun J, Jacobs EJ, Campbell PT, Gapstur SM. High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer. Gastroenterology 2011; 141:98-105, 105.e1. [PMID: 21586288 DOI: 10.1053/j.gastro.2011.04.004] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 03/25/2011] [Accepted: 04/08/2011] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Folate intake has been inversely associated with colorectal cancer risk in several prospective epidemiologic studies. However, no study fully assessed the influence of the high levels of folate that are frequently consumed in the United States as a result of mandatory folate fortification, which was fully implemented in 1998, and the recent increase in use of folate-containing supplements. There is evidence that consumption of high levels of folic acid, the form of folate used for fortification and in supplements, has different effects on biochemical pathways than natural folates and might promote carcinogenesis. METHODS We investigated the association between folate intake and colorectal cancer among 43,512 men and 56,011 women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort; 1023 were diagnosed with colorectal cancer between 1999 and 2007, a period entirely after folate fortification began. Cox proportional hazards regression was used to calculate multivariate hazards ratios (RR) and 95% confidence interval (CI). RESULTS Intake of high levels of natural folate (RRQ5vsQ1=0.86; 95% CI: 0.70-1.06; P trend=.12) or folic acid (RRQ5vsQ1=0.84; 95% CI: 0.68-1.03; P trend=.06) were not significantly associated with risk of colorectal cancer. Total folate intake was significantly associated with lower risk (RRQ5vsQ1=0.81; 95% CI: 0.66-0.99; P trend=.047). CONCLUSIONS Intake of high levels of total folate reduces risk of colorectal cancer; there is no evidence that dietary fortification or supplementation with this vitamin increases colorectal cancer risk.
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Affiliation(s)
- Victoria L Stevens
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303-1002, USA.
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Lal A, Ames BN. Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status. Mutagenesis 2011; 26:57-62. [PMID: 21164183 PMCID: PMC3107612 DOI: 10.1093/mutage/geq081] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Revised: 09/07/2010] [Accepted: 09/08/2010] [Indexed: 12/31/2022] Open
Abstract
Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motivating this effort is the idea that marginal micronutrient deficiencies lead to allocation of scarce cellular resources towards immediate survival at the expense of maintaining genomic integrity, placing the individual at greater risk for degenerative diseases and cancer in old age. The challenge in identifying an association between individual micronutrients and MN frequency stems from the complexity of human diet, simultaneous presence of multiple micronutrient deficiencies, variable genetic susceptibility and methodological difficulties. A unique model for studying MN in humans is provided by a group of haematological diseases, the chronic haemolytic anaemias associated with high reticulocyte count and absence of splenic function. These disorders may prove valuable for assessing the influence of micronutrient status once the effect of abnormal erythropoiesis on MN formation is adequately understood. Eventually, large population-based studies that can account for the baseline variability in MN frequency, lifestyle and genetic factors may be needed to uncover the DNA-damaging effect of poor diet. Understanding the link between micronutrient status and MN frequency will contribute towards determining optimal micronutrient intake to preserve long-term health.
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Affiliation(s)
- Ashutosh Lal
- Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
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Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, Koren G. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 2010; 35:2-10. [PMID: 21177150 DOI: 10.1016/j.canep.2010.11.004] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2010] [Revised: 11/04/2010] [Accepted: 11/17/2010] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Folic acid fortification and supplementation to prevent neural tube defects has led to concerns regarding increased risk of colorectal cancer. The results of existing studies have been inconclusive. The purpose was to examine the relationship between level of folate intake and the incidence of colorectal cancer. METHODS A systematic review and meta analysis were conducted. MEDLINE, Embase, and SCOPUS were searched from inception to October 2009 with the following search terms "folic acid," "folate", "colorectal cancer," "colon neoplasms," rectal neoplasms." Observational studies in adult populations were included that defined levels of folate intake and incidence of colorectal cancer. RESULT Out of 6427 references, 27 studies met our inclusion criteria. The summary risk estimate for case control studies comparing high versus low total folate intake was 0.85 (CI 95% 0.74-0.99) with no significant heterogeneity among studies. Similarly, for cohort studies, the resulting summary risk estimate for high versus low dietary folate intake was 0.92 (CI 95% 0.81-1.05) with no significant heterogeneity. However, defining what represents a higher intake of folic acid is difficult as there is variability in the upper limit of folic acid intake used in the studies. DISCUSSION These results suggest that higher folate intake levels offer a reduction in one of the perceived risks associated with developing colorectal cancer. These data can serve to help reassure women planning a pregnancy to increase folic intake during the preconception period to levels sufficient to prevent neural tube defects.
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Affiliation(s)
- Deborah A Kennedy
- The Motherisk Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada.
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Eussen SJPM, Vollset SE, Hustad S, Midttun Ø, Meyer K, Fredriksen A, Ueland PM, Jenab M, Slimani N, Boffetta P, Overvad K, Thorlacius-Ussing O, Tjønneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Weikert C, Pischon T, Linseisen J, Kaaks R, Trichopoulou A, Zilis D, Katsoulis M, Palli D, Pala V, Vineis P, Tumino R, Panico S, Peeters PHM, Bueno-de-Mesquita HB, van Duijnhoven FJB, Skeie G, Muñoz X, Martínez C, Dorronsoro M, Ardanaz E, Navarro C, Rodríguez L, VanGuelpen B, Palmqvist R, Manjer J, Ericson U, Bingham S, Khaw KT, Norat T, Riboli E. Plasma vitamins B2, B6, and B12, and related genetic variants as predictors of colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2010; 19:2549-61. [PMID: 20813848 PMCID: PMC3025315 DOI: 10.1158/1055-9965.epi-10-0407] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS Higher plasma concentrations of vitamins B2 and B6 are associated with a lower colorectal cancer risk. IMPACT 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.
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Affiliation(s)
- Simone J P M Eussen
- LOCUS for homocysteine and related vitamins, Institute of Medicine, University of Bergen, and Haukeland University Hospital, Bergen, Norway.
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Ames BN. Prevention of mutation, cancer, and other age-associated diseases by optimizing micronutrient intake. J Nucleic Acids 2010; 2010. [PMID: 20936173 PMCID: PMC2945683 DOI: 10.4061/2010/725071] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 07/30/2010] [Indexed: 12/31/2022] Open
Abstract
I review three of our research efforts which suggest that optimizing micronutrient intake will in turn optimize metabolism, resulting in decreased DNA damage and less cancer as well as other degenerative diseases of aging. (1) Research on delay of the mitochondrial decay of aging, including release of mutagenic oxidants, by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much of the population) accelerate molecular aging, including DNA damage, mitochondrial decay, and supportive evidence for the theory, including an in-depth analysis of vitamin K that suggests the importance of achieving optimal micronutrient intake for longevity. (3) The finding that decreased enzyme binding constants (increased Km) for coenzymes (or substrates) can result from protein deformation and loss of function due to an age-related decline in membrane fluidity, or to polymorphisms or mutation. The loss of enzyme function can be compensated by a high dietary intake of any of the B vitamins, which increases the level of the vitamin-derived coenzyme. This dietary remediation illustrates the importance of understanding the effects of age and polymorphisms on optimal micronutrient requirements. Optimizing micronutrient intake could have a major effect on the prevention of cancer and other degenerative diseases of aging.
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Affiliation(s)
- Bruce N Ames
- Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA
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Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology 2010; 138:2029-2043.e10. [PMID: 20420944 PMCID: PMC2947820 DOI: 10.1053/j.gastro.2010.01.057] [Citation(s) in RCA: 435] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Revised: 01/10/2010] [Accepted: 01/14/2010] [Indexed: 02/07/2023]
Abstract
Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.
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Affiliation(s)
- Andrew T Chan
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. <>
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Ames BN. Optimal micronutrients delay mitochondrial decay and age-associated diseases. Mech Ageing Dev 2010; 131:473-9. [PMID: 20420847 DOI: 10.1016/j.mad.2010.04.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2009] [Revised: 04/06/2010] [Accepted: 04/16/2010] [Indexed: 01/18/2023]
Abstract
Three of our research efforts are reviewed, which suggest that optimizing metabolism will delay aging and the diseases of aging in humans. (1) Research on delay of the mitochondrial decay of aging by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much of the population) accelerate molecular aging, including mitochondrial decay, and supportive evidence, including an analysis in depth of vitamin K, that suggests the importance of achieving optimal micronutrient intake for longevity. (3) The finding that decreased enzyme binding constants (increased Km) for coenzymes (or substrates) can result from protein deformation and loss of function due to loss of membrane fluidity with age, or to polymorphisms or mutation. The loss of enzyme function can be ameliorated by high doses of a B vitamin, which raises coenzyme levels, and indicates the importance of understanding the effects of age, or polymorphisms, on micronutrient requirements.
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Affiliation(s)
- Bruce N Ames
- Children's Hospital Oakland Research Institute, Nutrition and Metabolism Center, Oakland, CA 94609, USA.
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Abstract
BACKGROUND Folate, a water-soluble B vitamin and one of the major micronutrients in vegetables, is known as an essential factor for the de novo biosynthesis of purines and thymidylate, and it plays an important role in DNA synthesis and replication. Thus, folate deficiency results in ineffective DNA synthesis, and has been shown to induce the initiation and progression of colorectal cancer (CRC). Recently, the incidence of CRC in Korea has increased markedly in both men and women; this trend may be related to the adoption of a more 'westernized' lifestyle, including dietary habits. OBJECTIVE A hospital-based case-control study was conducted to examine the relationship between folate intake and the risk of CRC within a Korean population. METHODS A total of 596 cases and 509 controls, aged 30-79 years, were recruited from two university hospitals. Site- and sex-specific odds ratios (ORs) were estimated using logistic regression models. RESULTS Cases were more frequently found to have a family history of CRC among first-degree relatives, to consume more alcohol, to be more likely current smokers and less likely to participate in vigorous physical activity than the controls. In the overall data for men and women combined, multivariate ORs (95% confidence interval (CI), P for trend) comparing the highest vs the lowest quartile of dietary folate intake were: 0.47 (0.32-0.69, <0.001) for CRC, 0.42 (0.26-0.69, <0.001) for colon cancer and 0.48 (0.28-0.81, 0.007) for rectal cancer. An inverse association was also found in women with dietary folate intake: 0.36 (0.20-0.64, <0.001) for CRC, 0.34 (0.16-0.70, 0.001) for colon cancer and 0.30 (0.12-0.74, 0.026) for rectal cancer, but not in men. In addition, the total folate intake of women was strongly associated with a reduced risk of rectal cancer (OR, 0.38; 95% CI, 0.17-0.88; P for trend=0.04). CONCLUSION We found a statistically significant relationship between higher dietary folate intake and reduced risk of CRC, colon cancer and rectal cancer in women. A significant association is indicated between higher total folate intake and reduced risk of rectal cancer in women.
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Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SMT, Motola J, Laginha FM, Tsugane S. Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 2009; 9:122. [PMID: 19389261 PMCID: PMC2684745 DOI: 10.1186/1471-2407-9-122] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Accepted: 04/24/2009] [Indexed: 05/11/2023] Open
Abstract
Background Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated. Methods A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B6, and vitamin B12 were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for MTHFR A1298C and C677T, and MTR A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results Neither dietary intake of folate, vitamin B6, or vitamin B12 nor MTHFR polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; Ptrend = 0.010). The MTR 2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; Ptrend = 0.801), and statistically significant interactions with regard to risk were observed between the MTHFR A1298C polymorphism and folate (P = 0.024) or vitamin B6 (P = 0.043), and between the MTHFR C677T polymorphism and folate (P = 0.043) or vitamin B12 (P = 0.022). Conclusion MTHFR polymorphisms and dietary intake of folate, vitamin B6, and vitamin B12 had no overall association with breast cancer risk. However, increased risk was observed in total women with the MTR 2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between MTHFR polymorphisms and B vitamins, warrant further investigation.
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Affiliation(s)
- Enbo Ma
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.
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Shrubsole MJ, Yang G, Gao YT, Chow WH, Shu XO, Cai Q, Rothman N, Gao J, Wagner C, Zheng W. Dietary B vitamin and methionine intakes and plasma folate are not associated with colorectal cancer risk in Chinese women. Cancer Epidemiol Biomarkers Prev 2009; 18:1003-6. [PMID: 19240230 PMCID: PMC2677023 DOI: 10.1158/1055-9965.epi-08-1200] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Martha J Shrubsole
- Vanderbilt Epidemiology Center, Division of General Internal Medicine and Public Health, Vanderbilt University, Department of Biochemistry, School of Medicine, Nashville, TN 37203-1738, USA.
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Ishihara J, Inoue M, Iwasaki M, Sasazuki S, Tsugane S. Dietary calcium, vitamin D, and the risk of colorectal cancer. Am J Clin Nutr 2008; 88:1576-83. [PMID: 19064518 DOI: 10.3945/ajcn.2008.26195] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Calcium and vitamin D have a potential protective effect against colorectal cancer. OBJECTIVE We investigated the association of dietary intake of calcium and vitamin D with the risk of colorectal cancer in a large prospective cohort study of middle-aged Japanese men and women. DESIGN A total of 74 639 subjects (35 194 men and 39 445 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1999 to the end of 2004, during which time 761 cases of colorectal cancer (464 men, 297 women) were newly identified. Dietary intake of nutrients was calculated with the use of a 138-item self-administered food-frequency questionnaire. RESULTS After adjusting for potential confounding factors, the multivariate hazard ratio in the highest quintile of dietary calcium intake compared with the lowest was 0.71 (95% CI: 0.52, 0.98) among men. The association appeared to decrease considerably among subjects in the second quintile without a clear further dose-response relation (P for trend: 0.09). No association was seen among women. No statistically significant association with dietary vitamin D intake was seen in either men or women, although men in the highest dietary intake group of both nutrients had a lower risk than did men in the lowest group. CONCLUSIONS These findings indicate a potential decrease in the risk of colorectal cancer with higher dietary intake of calcium among middle-aged Japanese men, who have a relatively low dietary intake of calcium. Although vitamin D and colorectal cancer risk were not associated, potential effect modification between calcium and vitamin D on the risk of colorectal cancer was indicated.
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Affiliation(s)
- Junko Ishihara
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
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de Vogel S, Dindore V, van Engeland M, Goldbohm RA, van den Brandt PA, Weijenberg MP. Dietary folate, methionine, riboflavin, and vitamin B-6 and risk of sporadic colorectal cancer. J Nutr 2008; 138:2372-8. [PMID: 19022960 DOI: 10.3945/jn.108.091157] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Adequate intake of folate, methionine, riboflavin, and vitamin B-6 may prevent aberrant DNA methylation and thereby protect against colorectal cancer (CRC). However, previous epidemiological studies investigating associations between dietary intakes of these nutrients and CRC have been inconsistent. We investigated the associations between intakes of folate, methionine, riboflavin, and vitamin B-6 and CRC risk, accounting for the sublocalization of the tumor. Within the Netherlands Cohort Study on diet and cancer (n = 120,852), 2349 cases and 4168 subcohort members were available for data analyses from a follow-up period of 13.3 y after baseline. Gender-specific adjusted incidence rate ratios (RR) were calculated over quintiles of dietary intake in case-cohort analyses. Folate intake was not associated with CRC risk in either men or women. However, methionine was associated with decreased risk of proximal colon cancer among men (RR = 0.57 for highest vs. lowest quintile of intake; P-trend = 0.03) and rectal cancer among women (highest vs. lowest quintile; RR = 0.45; P-trend = 0.05). Riboflavin tended to be associated with decreased proximal colon cancer risk among women (RR = 0.61; P-trend = 0.07). Conversely, there was a strong positive association between vitamin B-6 and rectal cancer among women (RR = 3.57; P-trend = 0.01). Our findings suggest that relatively high methionine intake may protect against proximal colon cancer in men and rectal cancer in women but that folate may not have a protective effect. This is the 2nd prospective cohort study in which vitamin B-6 intake was associated with increased risk of rectal tumors in women, which might suggest that this vitamin enhances rectal cancer in women.
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Affiliation(s)
- Stefan de Vogel
- Departments of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
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Weinstein SJ, Albanes D, Selhub J, Graubard B, Lim U, Taylor PR, Virtamo J, Stolzenberg-Solomon R. One-carbon metabolism biomarkers and risk of colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 2008; 17:3233-40. [PMID: 18990766 PMCID: PMC2656360 DOI: 10.1158/1055-9965.epi-08-0459] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Folate intake has been associated with reduced colorectal cancer risk; however, few studies have prospectively examined circulating folate or other related one-carbon biomarkers. METHODS We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 50- to 69-year-old Finnish men to investigate associations between serum folate, vitamin B6, vitamin B12, riboflavin, and homocysteine and risk of colon and rectal cancers. Controls were alive and cancer-free at the time of case diagnosis and matched 1:1 on age and date of baseline fasting serum collection with cases (152 colon and 126 rectal cancers). Multivariate-adjusted odds ratios and 95% confidence intervals were calculated using conditional logistic regression. RESULTS Serum vitamin B6 was inversely associated with colon cancer [odds ratio, 0.30 (95% confidence interval, 0.11-0.82) in the highest versus lowest quintile]. An increased risk of colon cancer was suggested for men in the middle quintile of serum folate, but without indication of a dose-response relationship. None of the other serum biomarkers were associated with colon or rectal cancer, and we observed no interactions with alcohol consumption or methionine or protein intake. A priori combinations of the five one-carbon serum biomarkers provided no clear evidence to support a collective influence on colorectal cancer risk. CONCLUSIONS Our results support the hypothesis that higher vitamin B6 status may play a role in inhibiting colon cancer carcinogenesis; however, folate and other one-carbon related biomarkers were not associated with colon or rectal cancer.
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Affiliation(s)
- Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Nutritional Epidemiology Branch, Suite 320, 6120 Executive Boulevard, Bethesda, MD 20892, USA.
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Figueiredo JC, Levine AJ, Grau MV, Midttun O, Ueland PM, Ahnen DJ, Barry EL, Tsang S, Munroe D, Ali I, Haile RW, Sandler RS, Baron JA. Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation. Cancer Epidemiol Biomarkers Prev 2008; 17:2136-45. [PMID: 18708408 PMCID: PMC2518404 DOI: 10.1158/1055-9965.epi-07-2895] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION Our results suggest that high levels of PLP and B(2) may protect against colorectal adenomas.
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Affiliation(s)
- Jane C Figueiredo
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Harlyne J Norris Cancer Research Tower, 1450 Biggy Street Room 1509B, Los Angeles CA 90033, USA.
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Takeuchi PL, Antunes LMG, Takahashi CS. Modulation of doxorubicin-induced clastogenesis in Wistar rat bone marrow cells by vitamin B6. Arch Toxicol 2008; 82:869-73. [DOI: 10.1007/s00204-008-0308-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2007] [Accepted: 04/22/2008] [Indexed: 11/29/2022]
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de Vogel S, Bongaerts BWC, Wouters KAD, Kester ADM, Schouten LJ, de Goeij AFPM, de Bruïne AP, Goldbohm RA, van den Brandt PA, van Engeland M, Weijenberg MP. Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer. Carcinogenesis 2008; 29:1765-73. [PMID: 18339680 DOI: 10.1093/carcin/bgn074] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
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.
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Affiliation(s)
- Stefan de Vogel
- Department of Epidemiology, GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
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Plasma folate and risk of colorectal cancer in a nested case-control study: the Japan Public Health Center-based prospective study. Cancer Causes Control 2007; 19:67-74. [DOI: 10.1007/s10552-007-9071-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Accepted: 09/19/2007] [Indexed: 10/22/2022]
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