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Aslanov H, Bayramov B, Reissfelder C, Abdullayeva S, Mammadova Z, Aliyev F, Keese M, Hajibabazade J, Yagublu V. MTHFR Gene C677T Polymorphism (rs1801133) and Susceptibility to Colorectal Polyps in an Azerbaijani Population. J Clin Med 2023; 13:219. [PMID: 38202226 PMCID: PMC10779477 DOI: 10.3390/jcm13010219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/26/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Understanding the relationships between the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, colorectal polyps, and CRC risk can aid in advancing personalized medicine approaches in CRC prevention. The aim of the current study is to identify the association of C677T polymorphism of the MTHFR gene with the risk of colorectal polyps in the Azerbaijani population. METHODS This study included 125 patients with colon polyps and 155 healthy individuals as a control group. DNA was extracted from venous blood samples obtained from patients and healthy individuals, and the results were analyzed through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and agarose gel electrophoresis. RESULTS Wild-type, heterozygote, and homozygous mutant were revealed within 69 (55.2%), 49 (39.2%), and 7 (5.6%) patients and within 100 (64.5%), 45 (29%), and 10 (6.5%) healthy controls, respectively. However, no significant statistical associations were observed between CT and TT genotypes, dominant (CC vs. CT + TT) and recessive (CC + CT vs. TT) models, and the mutant T allele and disease risk. There were also no significant differences between patients and controls regarding age, sex, smoking and alcohol use. CONCLUSION Our research did not reveal any significant association between the MTHFR C677T polymorphism and susceptibility to colorectal polyps in the Azerbaijan population.
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Affiliation(s)
- Hazi Aslanov
- Department of Surgery, Scientific Center of Surgery after academician M.A.Topchubashov, Baku AZ1122, Azerbaijan;
| | - Bayram Bayramov
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku AZ1106, Azerbaijan; (B.B.); (Z.M.)
- Department of Natural Sciences, Western Caspian University, Baku AZ1001, Azerbaijan
| | - Christoph Reissfelder
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Shams Abdullayeva
- Department of Neurology, Westpfalz-Klinikum, 67655 Kaiserslautern, Germany;
| | - Zeynab Mammadova
- Laboratory of Human Genetics, Genetic Resources Institute of Ministry of Science and Education, Baku AZ1106, Azerbaijan; (B.B.); (Z.M.)
| | - Fikrat Aliyev
- Department of Pathomorphology, Scientific Center of Surgery after academician M.A.Topchubashov, Baku AZ1122, Azerbaijan;
| | - Michael Keese
- Department of Vascular Surgery, Theresienkrankenhaus, 68165 Mannheim, Germany;
| | - Javahir Hajibabazade
- Carver College of Medicine, University of Iowa, Bowen Science Building, 51 Newton, Road, Iowa City, IA 52242-1009, USA
| | - Vugar Yagublu
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
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Majumder A. Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment. Antioxidants (Basel) 2023; 12:1520. [PMID: 37627515 PMCID: PMC10451792 DOI: 10.3390/antiox12081520] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment of angiogenesis, whereas hydrogen sulfide (H2S) has been found to reverse this condition. Recent studies have shown that cancer cells need to produce a high level of endogenous H2S to maintain cell proliferation, growth, viability, and migration. However, any novel mechanism that targets this balance of Hcy and H2S production has yet to be discovered or exploited. Cells require homocysteine metabolism via the methionine cycle for nucleotide synthesis, methylation, and reductive metabolism, and this pathway supports the high proliferative rate of cancer cells. Although the methionine cycle favors cancer cells for their survival and growth, this metabolism produces a massive amount of toxic Hcy that somehow cancer cells handle very well. Recently, research showed specific pathways important for balancing the antioxidative defense through H2S production in cancer cells. This review discusses the relationship between Hcy metabolism and the antiapoptotic, antioxidative, anti-inflammatory, and angiogenic effects of H2S in different cancer types. It also summarizes the historical understanding of targeting antioxidative defense systems, angiogenesis, and other protective mechanisms of cancer cells and the role of H2S production in the genesis, progression, and metastasis of cancer. This review defines a nexus of diet and precision medicine in targeting the delicate antioxidative system of cancer and explores possible future therapeutics that could exploit the Hcy and H2S balance.
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Affiliation(s)
- Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94143, USA
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Wang Y, Du M, Vallis J, Shariati M, Parfrey PS, Mclaughlin JR, Wang PP, Zhu Y. The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival. Nutrients 2022; 14:4594. [PMID: 36364857 PMCID: PMC9658674 DOI: 10.3390/nu14214594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. METHODS This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina's integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. RESULTS The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. CONCLUSIONS Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.
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Affiliation(s)
- Yu Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Meizhi Du
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Jillian Vallis
- Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
| | - Matin Shariati
- Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
| | - Patrick S. Parfrey
- Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
| | - John R. Mclaughlin
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Peizhong Peter Wang
- Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
| | - Yun Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
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Genetic impact of methylenetetrahydrofolate reductase (MTHFR) polymorphism on the susceptibility to colorectal polyps: a meta-analysis. BMC MEDICAL GENETICS 2019; 20:94. [PMID: 31146742 PMCID: PMC6543585 DOI: 10.1186/s12881-019-0822-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 05/09/2019] [Indexed: 12/31/2022]
Abstract
Background There are several studies with inconsistent conclusions regarding the association between the rs1801133 and rs1801131 polymorphisms within the MTHFR (methylenetetrahydrofolate reductase) gene and colorectal polyp risk. This discrepancy led us to assess the genetic impact of the two polymorphisms on the susceptibility to colorectal polyps. Methods A meta-analysis was carried out for quantitative synthesis. According to the inclusion/exclusion criteria, we retrieved, screened and selected all published articles related to colorectal polyps and the MTHFR rs1801133 and rs1801131 polymorphisms. The P value of association test, RRs (risk ratios) and 95% CIs (confidence intervals) were mainly produced. Results A total of twenty-three case-control studies were included from twenty-two eligible articles. Pooling the results of both rs1801133 and rs1801131 polymorphisms in the overall population suggested a nonsignificant association between colorectal polyp cases and controls, in that all P values in the test of association were larger than 0.05. Nevertheless, pooling results in the “UK” subgroup of rs1801131, comprising five studies (1257 cases/1407 controls), indicated an elevated risk in colorectal polyp cases in comparison with controls, under the genetic models of CC vs. AA (P = 0.032, RR = 1.27, 95% CIs = 1.02, 1.57) and CC vs. AA+AC (P = 0.036, RR = 1.27, 95% CIs = 1.02, 1.60). Conclusion The C/C genotype of MTHFR rs1801131 is more likely to be a genetic risk factor for colorectal polyps in the UK region, although this finding should be verified with a larger sample size. Electronic supplementary material The online version of this article (10.1186/s12881-019-0822-y) contains supplementary material, which is available to authorized users.
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Hasan T, Arora R, Bansal AK, Bhattacharya R, Sharma GS, Singh LR. Disturbed homocysteine metabolism is associated with cancer. Exp Mol Med 2019; 51:1-13. [PMID: 30804341 PMCID: PMC6389897 DOI: 10.1038/s12276-019-0216-4] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 11/30/2022] Open
Abstract
Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5–15 μmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 μmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed. Cancer can be added to the wide range of diseases known to be associated with elevated blood levels of the small amino acid homocysteine. Abnormally high levels of this compound are already known to contribute to conditions including cardiovascular problems, neurodegenerative diseases, neural tube defects, Down’s syndrome, diabetes and megaloblastic anemia. This review, by Laishram R. Singh and colleagues at the University of Delhi, India, concludes that disturbed homocysteine metabolism is associated with many forms of human cancer. The authors discuss a range of genetic, epigenetic and environmental factors that may be involved in the cause and effect relationships between homocysteine metabolism and cancer. It is particularly interesting that low folate (vitamin B9) levels result in high homocysteine levels, and vice versa. Further research may yield insights leading to new forms of cancer treatment and diagnosis.
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Affiliation(s)
- Tauheed Hasan
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Reetika Arora
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Aniket Kumar Bansal
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Reshmee Bhattacharya
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
| | - Gurumayum Suraj Sharma
- Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110 007, India
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Cui LH, Shin MH, Kweon SS, Kim HN, Song HR, Piao JM, Choi JS, Shim HJ, Hwang JE, Kim HR, Park YK, Kim SH. Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population. BMC Cancer 2010; 10:236. [PMID: 20504332 PMCID: PMC2893109 DOI: 10.1186/1471-2407-10-236] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Accepted: 05/26/2010] [Indexed: 12/17/2022] Open
Abstract
Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.
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Affiliation(s)
- Lian-Hua Cui
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea
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Eussen SJPM, Vollset SE, Igland J, Meyer K, Fredriksen A, Ueland PM, Jenab M, Slimani N, Boffetta P, Overvad K, 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, Berrino F, Vineis P, Tumino R, Panico S, Peeters PHM, Bueno-de-Mesquita HB, van Duijnhoven FJB, Gram IT, Skeie G, Lund E, González CA, Martínez C, Dorronsoro M, Ardanaz E, Navarro C, Rodríguez L, Van Guelpen B, Palmqvist R, Manjer J, Ericson U, Bingham S, Khaw KT, Norat T, Riboli E. Plasma folate, related genetic variants, and colorectal cancer risk in EPIC. Cancer Epidemiol Biomarkers Prev 2010; 19:1328-40. [PMID: 20447924 PMCID: PMC2880712 DOI: 10.1158/1055-9965.epi-09-0841] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort. METHODS In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. RESULTS Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C-->T, MTHFR1298A-->C, MTR2756A-->G, MTRR66A-->G, and MTHFD11958G-->A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC=1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC=0.74 (0.39-1.37); 0.34]. The SLC19A180G-->A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01]. CONCLUSIONS This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. IMPACT Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.
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Affiliation(s)
- Simone J P M Eussen
- LOCUS for homocysteine and related vitamins, Institute of Medicine, Section for Pharmacology, Department of Internal Medicine, University of Bergen, and Haukeland University Hospital, 5021 Laboratory Building, 9th floor, Bergen, Norway.
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Taioli E, Garza MA, Ahn YO, Bishop DT, Bost J, Budai B, Chen K, Gemignani F, Keku T, Lima CSP, Le Marchand L, Matsuo K, Moreno V, Plaschke J, Pufulete M, Thomas SB, Toffoli G, Wolf CR, Moore CG, Little J. Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review. Am J Epidemiol 2009; 170:1207-21. [PMID: 19846566 DOI: 10.1093/aje/kwp275] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.
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Affiliation(s)
- E Taioli
- SUNY Downstate Medical Center, Brooklyn, New York 11203, USA.
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Levine AJ, Wallace K, Tsang S, Haile RW, Saibil F, Ahnen D, Cole BF, Barry EL, Munroe DJ, Ali IU, Ueland P, Baron JA. MTHFR genotype and colorectal adenoma recurrence: data from a double-blind placebo-controlled clinical trial. Cancer Epidemiol Biomarkers Prev 2008; 17:2409-15. [PMID: 18768511 DOI: 10.1158/1055-9965.epi-07-2670] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double- blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared with those with two wild-type alleles, the relative risk for advanced adenoma was 0.75 (95% CI, 0.36-1.55) for the MTHFR 677 TT genotype and 1.16 (95% CI, 0.58-2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk.
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Affiliation(s)
- A Joan Levine
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Murphy G, Sansbury LB, Cross AJ, Stolzenberg-Solomon R, Laiyemo A, Albert PS, Wang Z, Schatzkin A, Lehman T, Kalidindi A, Modali R, Lanza E. Folate and MTHFR: risk of adenoma recurrence in the Polyp Prevention Trial. Cancer Causes Control 2008; 19:751-8. [PMID: 18322814 DOI: 10.1007/s10552-008-9137-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Accepted: 02/15/2008] [Indexed: 11/26/2022]
Abstract
BACKGROUND Low dietary folate intake has been associated with colorectal cancer risk and adenoma recurrence. A C/T transition at position 677 in the gene encoding methlylenetetrahydrofolate reductase (MTHFR C677T) has been reported to interact with folate intake to modulate colorectal adenoma recurrence or cancer risk. METHODS We investigated the association between MTHFR, total folate, and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. We compared 625 individuals with any adenoma recurrence after 4 years (266 individuals with multiple (> or =2) recurrent adenomas and 101 individuals with advanced adenoma recurrence) to 978 individuals with no adenoma recurrence. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. We also investigated effect modification of the MTHFR genotype associations by total folate intake. RESULTS In general, no statistically significant associations were found between quartile of folate intake (dietary or total) and adenoma recurrence. The MTHFR CT genotype was associated with a significantly increased risk of multiple adenoma recurrence (OR: 1.34, 95% CI: 1.00, 1.81). No significant interaction was noted for total folate and MTHFR genotype, though an increased risk of recurrence noted for the MTHFR CT genotype was statistically significant only for those individuals with below median intake of total folate. CONCLUSION We report that the MTHFR 677 CT genotype was associated with increased risk of adenoma recurrence (specifically multiple adenoma recurrence) 4 years after polypectomy.
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Affiliation(s)
- Gwen Murphy
- Cancer Prevention Fellowship Program, Office of Preventive Oncology, Bethesda, MD, USA.
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Ashktorab H, Begum R, Akhgar A, Smoot DT, Elbedawi M, Daremipouran M, Zhao A, Momen B, Giardiello FM. Folate status and risk of colorectal polyps in African Americans. Dig Dis Sci 2007; 52:1462-70. [PMID: 17372834 DOI: 10.1007/s10620-006-9236-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2005] [Accepted: 01/30/2006] [Indexed: 12/14/2022]
Abstract
Dietary folate status appears to influence risk for colorectal cancer possibly by alterations in DNA methylation and nucleotide precursor pools. Polymorphisms (677C-->T and 1298A-->C) in methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, determines enzyme activity. The frequency of polymorphisms in the gene varies extensively in different populations. We sought to determine the association between folate status, folate metabolism, DNA methylation, tobacco, alcohol consumption, and the risk of colorectal adenomas in African Americans. Among 58 patients who underwent a clinically indicated colonoscopy, 23 patients with histology confirmed colorectal polyps and 35 patients without were recruited for a case-control study. Blood samples were collected from fasting patients for determination of serum and red blood cell (RBC) folate, homocysteine, vitamin B(12), and methylation status. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique was performed to identify the MTHFR 677 C-->T polymorphism and specific PCR was used to analyze adenomatous polyposis coli (APC) gene-promoter sequence methylation. Among 23 cases, 49 polyps (adenomatous, n = 41 and hyperplastic, n= 8) were identified. Twenty-eight (57%) of the polyps were on the left side and 21 (42%) were on the right side of the colon. There was no association between the presence of colon polyps and levels of folate (serum, RBC), vitamin B(12), or homocysteine. Forty-eight individuals (84%) were homozygous for 677 CC. Of these individuals, 18 (37.5%) had >/=1 colorectal polyps, whereas 30 (62.5%) had no polyps. Nine individuals were heterozygous for 677 CT, and 4 (44%) of these individuals had colon polyps. Eighty-eight percent of the APC gene-promoter sequences tested using peripheral blood DNA from patients were unmethylated. Among the individuals who showed APC methylation, 66% had polyps; 33% were polyp free using their blood DNA. There was highly significant association between smoking and alcohol consumption with the presence of a colon polyp (P= .0006 and P= .05, respectively). In conclusion, the lack of the 677 TT may be a significant risk factor for colon neoplasm in the African-American population. Smoking and alcohol consumption were found to be risk factors for colon polyps. APC gene-promoter sequence methylation found in peripheral blood may be an indicator of risk for polyp formation and an important screening tool.
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Affiliation(s)
- H Ashktorab
- Cancer Center and Department of Medicine, Howard University College of Medicine, Washington, DC 20060, USA.
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12
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van den Donk M, van Engeland M, Pellis L, Witteman BJM, Kok FJ, Keijer J, Kampman E. Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2007; 16:327-33. [PMID: 17301267 DOI: 10.1158/1055-9965.epi-06-0810] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Methylation of the promoter region of tumor suppressor genes is increasingly recognized to play a role in cancer development through silencing of gene transcription. We examined the associations between dietary folate intake, MTHFR C677T genotype, and promoter methylation of six tumor suppressor and DNA repair genes. Patients with colorectal adenoma (n = 149) and controls (n = 286) with folate intake in the upper or lower tertile with the CC or TT genotype were selected from a case-control study. Methylation-specific PCRs were conducted on colorectal adenoma specimens. The percentages of promoter methylation ranged from 15.7% to 64.2%. In case-case comparisons, folate was inversely associated with promoter methylation, especially among TT homozygotes. Case-control comparisons suggested that folate was not associated with the occurrence of adenomas with promoter methylation, and increased the risk of unmethylated adenomas, especially in TT homozygotes. The interactions between folate and MTHFR genotype were most pronounced for O(6)-MGMT: compared with CC homozygotes with low folate intake, the adjusted odds ratios (95% confidence interval) of having a methylated O(6)-MGMT promoter were 3.39 (0.82-13.93) for TT homozygotes with low folate intake and 0.37 (0.11-1.29) for TT homozygotes with high folate intake (P interaction = 0.02); the odds ratios for the occurrence of adenomas without methylation were 0.57 (0.16-2.11) for TT homozygotes with low folate intake and 3.37 (1.17-9.68) for TT homozygotes with high folate intake (P interaction = 0.03). In conclusion, folate intake seems to be inversely associated with promoter methylation in colorectal adenomas in case-case comparisons, and was positively associated with the occurrence of adenomas without promoter methylation in case-control comparisons, especially for TT homozygotes.
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Affiliation(s)
- Maureen van den Donk
- Division of Human Nutrition, Wageningen University, P.O. Box 8129, NL-6700 EV Wageningen, the Netherlands
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13
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Hekim N, Ergen A, Yaylim I, Yilmaz H, Zeybek U, Oztürk O, Isbir T. No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer. Cell Biochem Funct 2007; 25:115-7. [PMID: 16134079 DOI: 10.1002/cbf.1274] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20), that reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the homocysteine to methionine conversion. MTHFR is a key enzyme that regulates folate metabolism which has an important role in DNA synthesis, DNA repair and methylation. The association between MTHFR C677T polymorphism and breast cancer has been investigated in several previous studies. Some researchers have shown an association between C677T polymorphism and breast cancer, but not all researchers found this association however. This study was designed to investigate, in the Turkish population, the association of MTHFR C677T polymorphism and breast cancer. Forty women patients with breast cancer and 68 healthy women were included in the study. MTHFR gene polymorphism was determined by the PCR-RFLP method. SPSS 10.0 for windows was used to determine statistical significance. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. It was found that the frequencies of MTHFR polymorphism were 55%, 40%, 5% for CC, CT, TT genotype in patients and 56%, 38%, 6% in healthy controls respectively. Furthermore, association was observed among family history, metastatic risk and MTHFR genotypes in patients. Our data fail to support a relationship between MTHFR C677T and the risk for breast cancer. It may be that there are ethnic differences in terms of this relationship.
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Affiliation(s)
- Nezih Hekim
- Dr Pakize I Tarzi Laboratories, Istanbul, Turkey
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14
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Huang Y, Han S, Li Y, Mao Y, Xie Y. Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis. J Hum Genet 2006; 52:73-85. [PMID: 17089070 DOI: 10.1007/s10038-006-0082-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2006] [Accepted: 10/04/2006] [Indexed: 12/27/2022]
Abstract
Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls) showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval (CI) 0.89-0.98, P=0.22 (for heterogeneity)] for a worldwide population. Meta-analyses of other genetic contrasts suggested that the 677T allele is more likely to affect CRC in a recessive genetic model worldwide (P<0.0001, OR=0.86; 95% CI 0.76-0.96, P=0.06) and in Asians (P=0.0005, OR=0.75; 95% CI 0.64-0.88, P=0.71). Similarly, we found a significantly decreased risk of CRC for 1298C polymorphism (4,764 CRC patients and 6,592 controls) for a recessive genetic model worldwide (P=0.005, OR=0.81; 95% CI 0.70-0.94, P=0.40) and in Caucasians (P=0.04, OR=0.75 95% CI 0.57-0.99, P=0.35). No evidence of association of C677T (4,616 patients and 6,338 controls) and A1298C (1,272 patients and 1,684 controls) with colorectal adenoma were found. The evidence accumulated suggests that MTHFR may represent a low-penetrance susceptible gene for CRC, and that the two polymorphisms might protect against colorectal adenoma developing into cancer. A larger single study is required to further evaluate gene-gene and gene-environment interactions for MTHFR polymorphisms and the cancer risk in a specific population.
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Affiliation(s)
- Yan Huang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China
| | - Shizhong Han
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China
| | - Yao Li
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China
| | - Yumin Mao
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China
| | - Yi Xie
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, 200433, People's Republic of China.
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15
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Mitrou PN, Watson MA, Loktionov AS, Cardwell C, Gunter MJ, Atkin WS, Macklin CP, Cecil T, Bishop TD, Primrose J, Bingham SA. MTHFR (C677T and A1298C) Polymorphisms and Risk of Sporadic Distal Colorectal Adenoma in the UK Flexible Sigmoidoscopy Screening Trial (United Kingdom). Cancer Causes Control 2006; 17:793-801. [PMID: 16783607 DOI: 10.1007/s10552-006-0016-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Accepted: 02/01/2006] [Indexed: 11/30/2022]
Abstract
OBJECTIVE The purpose of this study was to further evaluate the role of low activity MTHFR variants as well as to explore interactive effects between alcoholic drink consumption and MTHFR variants and risk of distal colorectal adenomatous polyps. METHODS We examined the relationship between MTHFR C677T and A1298C gene polymorphisms and risk of distal adenomas in one of the largest case control studies of 946 polyp-free controls and 894 cases, all participants of the UK Flexible Sigmoidoscopy Screening Trial (UKFSS). RESULTS Investigation of the effect of the MTHFR C677T polymorphism in this large UKFSS study revealed no overall association on adenoma risk (P>0.05). However the MTHFR 1298C allele was linked, for the first time, to high risk adenomas, although in males only (odds ratio (OR) for A/C+C/C compared with A/A 1.55; 95% confidence interval (CI), 1.08-2.22; P=0.018). CONCLUSIONS In this, the largest study of these polymorphisms in relation to colorectal adenoma, there was no evidence for an interaction with alcohol in combination with the variant forms of MTHFR (P>0.05).
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Affiliation(s)
- Panagiota N Mitrou
- Dunn Human Nutrition Unit, MRC/Wellcome Trust Building, Hills Road, Cambridge, CB2 2XY, UK
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16
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Kono S, Chen K. Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Sci 2005; 96:535-42. [PMID: 16128738 PMCID: PMC11160001 DOI: 10.1111/j.1349-7006.2005.00090.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA methylation and synthesis. Two functional, common polymorphisms (C677T and A1298C) are known in the MTHFR gene. MTHFR activity is lowered in individuals with the 677TT genotype and is somewhat reduced in those with the 1298CC genotype. We reviewed the consistency of reported associations of these polymorphisms with colorectal cancer and adenoma with consideration of the effects of nutritional status. A total of 16 studies have addressed the association between MTHFR C677T polymorphism and colorectal cancer in 10 countries. Decreased risk of colorectal cancer associated with the 677TT genotype has fairly consistently been observed, with few exceptions. This decrease was observable in people with either high or low folate status. Alteration in the thymidylate pool associated with MTHFR activity is postulated as an underlying mechanism. Studies on the A1298C polymorphism are limited, and their results are variable. Almost all of seven studies of colorectal adenoma have found no association between C677T polymorphism and adenoma, but the 677TT genotype seems to be related to increased risk when folate status is poor. Reduced availability of methyl groups for DNA methylation might be more relevant to adenoma formation. Although the underlying mechanisms still remain to be clarified, epidemiological findings regarding MTHFR C677T polymorphism provide strong evidence that adequate folate status confers protection from colorectal cancer.
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Affiliation(s)
- Suminori Kono
- Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
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17
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van den Donk M, Buijsse B, van den Berg SW, Ocké MC, Harryvan JL, Nagengast FM, Kok FJ, Kampman E. Dietary intake of folate and riboflavin, MTHFR C677T genotype, and colorectal adenoma risk: a Dutch case-control study. Cancer Epidemiol Biomarkers Prev 2005; 14:1562-6. [PMID: 15941973 DOI: 10.1158/1055-9965.epi-04-0419] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We investigated the associations between dietary intake of folate and vitamin B2, MTHFR C677T genotype, and colorectal adenomas in a Dutch case-control study. Data of cases with at least one histologically confirmed colorectal adenoma (n = 768) and controls with no history of any type of colorectal polyp (n = 709) were included. Dietary intake was assessed using a food-frequency questionnaire. Multivariable models included age and, if appropriate, dietary folate and calcium intake. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest compared with the lowest sex-specific tertile of intake were 1.32 (95% CI, 1.01-1.73) for folate and 0.51 (95% CI, 0.36-0.73) for vitamin B2. Folate seemed to be a risk factor, especially when vitamin B2 intake was low; vitamin B2 was inversely associated with adenomas, especially with relatively high folate intake. No association was observed between MTHFR C677T genotype and colorectal adenomas. The inverse association between vitamin B2 intake and colorectal adenoma risk seemed to be more pronounced among those with the MTHFR TT genotype. We conclude that this study does not provide evidence for a decreased colorectal adenoma risk for subjects with high dietary intake of folate. It suggests, however, an inverse association between vitamin B2 and colorectal adenomas, which may be more relevant for those with the MTHFR TT genotype.
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Affiliation(s)
- Maureen van den Donk
- Division of Human Nutrition (bode 62), Wageningen University, P.O. Box 8129, NL-6700 EV Wageningen, Netherlands
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18
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Hirose M, Kono S, Tabata S, Ogawa S, Yamaguchi K, Mineshita M, Hagiwara T, Yin G, Lee KY, Tsuji A, Ikeda N. Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study. Cancer Sci 2005; 96:513-8. [PMID: 16108833 PMCID: PMC11159593 DOI: 10.1111/j.1349-7006.2005.00077.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.
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Affiliation(s)
- Maho Hirose
- Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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19
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Bollheimer LC, Buettner R, Kullmann A, Kullmann F. Folate and its preventive potential in colorectal carcinogenesis. Crit Rev Oncol Hematol 2005; 55:13-36. [PMID: 15927841 DOI: 10.1016/j.critrevonc.2004.12.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Revised: 12/01/2004] [Accepted: 12/22/2004] [Indexed: 12/31/2022] Open
Abstract
Based on a 15-year old hypothesis, it is believed that an adequate ingestion of folate vitamins decreases, whereas a nutritional depletion of folate increases the risk of colorectal cancer. The present article reviews the efforts to provide biochemical and epidemiological evidence for folate as a chemopreventive agent against colorectal carcinogenesis. BIOLOGICAL EVIDENCE: Tetrahydrofolates govern the intracellular one-carbon metabolism and account for proper DNA biosynthesis and macromolecular modification. Numerous experimental studies traced different molecular pathways and tried to link folate depletion with DNA instability and/or mutagenesis. However, none of the proposed underlying molecular mechanisms appear clearly defined. EPIDEMIOLOGICAL EVIDENCE: Numerous case-control and prospective studies have been conducted on folate and colorectal cancer, which all together miss a clinical bottom line. The recommendation of folate intake to prevent colorectal cancer is therefore not evidence-based.
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20
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Chen K, Jiang Q, Ma X, Li Q, Yao K, Yu W, Zheng S. Alcohol drinking and colorectal cancer: A population-based prospective cohort study in China. Eur J Epidemiol 2005; 20:149-54. [PMID: 15792281 DOI: 10.1007/s10654-004-2953-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
STUDY OBJECTIVE To asses the association between alcohol consumption and the risk of colorectal cancer (CRC) in the Chinese population. DESIGN A population-based prospective cohort study was initiated from the colorectal cancer screening population in Jiashan County in 1989-1990. The drinking habits of individuals were investigated with demographic information. SETTING A cohort study was followed-up from 1st May 1990 to 1st January 2001 and censored at the date of diagnosis of CRC, at death from any causes, or at 1st January 2001, whichever came first, and the person-time was computed. PARTICIPANTS Two hundred and forty two CRC patients were diagnosed during the study period and 64,100 individuals finished the follow-up. RESULTS The distribution of sex, smoking status, occupation, education level and marital status were all significantly different among different drinking habits at baseline. When the above factors were adjusted, no significant association was observed between alcohol consumption and the risk of CRC. Exclusion of individuals diagnosed cancer less than 1 year after the examination date did not alter the strength of an alcohol-CRC relationship. Further analysis in sex strata also did not show a significant relationship. CONCLUSIONS Alcohol drinking may not be associated with a higher risk of CRC in the Chinese population.
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Affiliation(s)
- Kun Chen
- Department of Epidemiology and Health Statistics, Zhejiang University school of Medicine, Hangzhou, China.
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21
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Abstract
AIM: To clarify the influence of genetic polymorphisms on colorectal cancer.
METHODS: The results of 42 related studies from 1990 to 2001 were analyzed by meta-analysis. Mantel-Haenzel fixed-effect model or Dersimonian-Laird random-effect model and ReviewManager 4.1 statistical program were applied in processing the data.
RESULTS: Meta analysis of these studies showed that GSTT1 deletion (pooled OR = 1.42), N-acetyltransferase 2 (NAT2)-rapid acetylator phenotype and genotye (pooled OR = 1.08) and NAT2-rapid acetylator phenotype (pooled OR = 1.15) had a significantly increased risk for colorectal cancer (P<0.05), other genotypes like GSTM1 deletion, GSTP1 1le105Val, NAT1*10, NAT2-rapid acetylator genotype CYP1A1 L1e462Val, CYP1A1 MspI*C, MTHFR C677T and MTR A2759G had no significant relationship with colorectal cancer (P>0.05).
CONCLUSION: Risks for colorectal cancer are significantly associated with the genetic polymorphisms of GSTT1 deletion, NAT2-rapid acetylator phenotype and genotye and NAT2-rapid acetylator phenotype.
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Affiliation(s)
- Kun Chen
- Department of Epidemiology and Health Statistics, School of Medicine, Zhejiang University, Hangzhou 310031, Zhejiang Province, China.
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22
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Giovannucci E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 2004; 134:2475S-2481S. [PMID: 15333745 DOI: 10.1093/jn/134.9.2475s] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
A growing body of evidence implicates alcohol intake as a risk factor for colorectal cancer. Until recently, most of the data were based on epidemiologic data that examined alcohol intake in relation to risk of colorectal neoplasia, but the evidence has now been broadened by recent molecular studies on mechanisms. In particular, a number of observations strongly support a role for alcohol acting through disruptions in one-carbon metabolism. Excessive alcohol intake is a fairly consistent risk factor for colorectal neoplasia in most studies, and studies show much higher risks of colorectal neoplasia in those with high alcohol and low folate than with high alcohol or low folate individually. Interactions between high alcohol-low folate and the MTHFR677TT genotype with risk of colorectal neoplasia suggest that alcohol is acting through its effects on one-carbon metabolism because the combination of high alcohol-low folate and the MTHFR677TT genotype are related to markedly elevated serum levels of homocysteine and to DNA hypomethylation. In addition, in Japanese studies, consumers of alcohol possessing the ALDH2*2 allele, who have very elevated levels of acetaldehyde, are at high risk for colorectal cancer. The relatively high prevalence of the ALDH2*2 allele may thus account for the stronger association between alcohol and colorectal neoplasia that is frequently observed in studies in Japanese populations. Further research integrating studies with more detailed data on alcohol intake levels and patterns, folate and other related nutrient status, and relevant genotypes may help clarify unresolved questions regarding the health consequences of moderate to high alcohol drinking.
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Affiliation(s)
- Edward Giovannucci
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston MA 02115, USA.
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23
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Peyrin-Biroulet L, Barraud H, Ancel D, Petit-Laurent F, Bigard MA, Gueant JL, Bronowicki JP. Métabolisme des folates et cancérogenèse colorectale. ACTA ACUST UNITED AC 2004; 28:582-92. [PMID: 15243392 DOI: 10.1016/s0399-8320(04)95015-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Laurent Peyrin-Biroulet
- Service d'Hépato-Gastroentérologie et Laboratoire de Pathologie Cellulaire et Moléculaire en Nutrition-INSERM E00-14, CHU Nancy-Brabois, allée du Morvan, 54511 Vandoeuvre-lès-Nancy
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24
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Zhu Y, Spitz MR, Amos CI, Lin J, Schabath MB, Wu X. An evolutionary perspective on single-nucleotide polymorphism screening in molecular cancer epidemiology. Cancer Res 2004; 64:2251-7. [PMID: 15026370 DOI: 10.1158/0008-5472.can-03-2800] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Given that there are millions of single-nucleotide polymorphisms (SNPs) in the entire human genome, a major difficulty faced by scientists in planning costly population-based genotyping is to choose target SNPs that are most likely to affect phenotypic functions and ultimately contribute to disease development. Although it is widely accepted that sequences with important functionality tend to be less variable across species because of selective pressure, to what extent evolutionary conservation is mirrored by epidemiological outcome has never been demonstrated. In this study, we surveyed odds ratios detected for 46 SNPs in 39 different cancer-related genes from 166 molecular epidemiological studies. The conservation levels of amino acid that these SNPs affected were calculated as a tolerance index by comparing sequences from different species. Our results provide evidence of a significant relationship between the detected odds ratios associated with cancer risk and the conservation levels of the SNP-affected amino acids (P = 0.002; R(2) = 0.06). Tolerance indices were further calculated for 355 nonsynonymous SNPs identified in 90 human DNA repair genes, of which 103 caused amino acid changes in very conserved positions. Our findings support the concept that SNPs altering the conserved amino acids are more likely to be associated with cancer susceptibility. Using such a molecular evolutionary approach may hold great promise for prioritizing SNPs to be genotyped in future molecular epidemiological studies.
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Affiliation(s)
- Yong Zhu
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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25
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Abstract
Colorectal cancer is a disease with a high mortality at present, due to the late stage at which many cases present. Attention is therefore focusing on preventative strategies for colorectal cancer given that polyps appear to be identifiable and treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer and there is a good case for endoscopic screening of the general population. However, this will require a large amount of manpower and resources and its success will also depend on the overall compliance of the population. Epidemiological studies have shown that individuals reporting a regular intake of aspirin and other non-steroidal anti-inflammatory drugs have a reduced risk of developing colorectal polyps and cancer. Similarly, a number of natural substances, such as calcium and folate, when supplemented regularly in the diet, have also been linked to a possible decreased incidence of colorectal cancer. This has led to the concept of using such agents to reduce the number of cases of colorectal cancer. In this article, we review the current evidence for the use of these and other agents for the chemoprevention of colorectal cancer, together with theories as to their possible mechanisms of action.
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Affiliation(s)
- E D J Courtney
- Gastroenterology Medicine Division, St George's Hospital Medical School, London, UK.
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26
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Little J, Sharp L, Duthie S, Narayanan S. Colon cancer and genetic variation in folate metabolism: the clinical bottom line. J Nutr 2003; 133:3758S-3766S. [PMID: 14608111 DOI: 10.1093/jn/133.11.3758s] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
So far, evidence for the relation between folate intake and colorectal cancer has been insufficient to lead to specific public health interventions. In principle, data on the relation between genetic variation in folate metabolism and colorectal neoplasia could be used to corroborate the data on the relation between folate intake or status and the disease, strengthening the evidence base for primary prevention. Issues in considering the relation between a health outcome and genetic variation in metabolism of nutrients or other food components include knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction. Overall homozygosity for MTHFR variant genotypes is associated with a reduced risk of colorectal cancer, the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and methylenetetrahydrofolate reductase in DNA synthesis. Folate and related nutrients may be important after adenoma formation. A challenge for the future is to characterize the effects of multiple genes influencing folate metabolism. Limited data for colorectal cancer suggest that the effect of a low folate diet overrides the effect of genotype, but two studies of adenomas suggested the opposite. Another potential role of information on genetic variation in folate metabolism is in the management of colorectal cancer but most studies have been small, have included selected patient groups, and have made limited adjustment for potentially important factors.
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Affiliation(s)
- Julian Little
- Epidemiology Group, Department of Medicine & Therapeutics, University of Aberdeen, UK.
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27
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Pufulete M, Al-Ghnaniem R, Leather AJM, Appleby P, Gout S, Terry C, Emery PW, Sanders TAB. Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 2003; 124:1240-8. [PMID: 12730865 DOI: 10.1016/s0016-5085(03)00279-8] [Citation(s) in RCA: 205] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Low folate intake may increase risk for colorectal cancer by inducing DNA hypomethylation. This study reports the influence of folate status, DNA methylation, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-->T and 1298A-->C), methionine synthase (MS 2756A-->G), and cystathionine-beta-synthase (CBS 844ins68) on risk for developing colorectal neoplasia. METHODS Thirty-five patients with adenoma, 28 patients with cancer, and 76 controls were recruited for a case control study. Recruitment consent rate was 98%. Blood samples were obtained for determination of blood folates, vitamin B(12), homocysteine, DNA methylation, and genotypes. Tissue biopsy samples were obtained at colonoscopy for determination of DNA methylation in colonic mucosa. Folate status was assessed by constructing a score from estimates of dietary intake and serum and erythrocyte folate. RESULTS Cancer patients had 26% lower folate status (95% confidence interval [CI]: 6% to 44%, P = 0.01) and 21% lower serum vitamin B(12) concentration (95% CI: -38% to 1%, P = 0.06) compared with controls. [(3)H] methyl incorporation into colonic DNA was 26% higher in patients with adenoma (95% CI: 8% to 56%, P = 0.009) and 30% higher in patients with cancer (95% CI: -3% to 48%, P = 0.08) compared with controls. High folate status was associated with decreased risk for cancer (P = 0.01 for trend). Colonic and leukocyte DNA hypomethylation were associated with increased risk for adenoma (P = 0.02 and P = 0.01 for trend, respectively) and a nonsignificantly increased risk for cancer (P = 0.09 and P = 0.08 for trend, respectively). CONCLUSIONS Low folate status and DNA hypomethylation are associated with colorectal neoplasia.
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Affiliation(s)
- Maria Pufulete
- Nutrition Food and Health Research Centre, Department of Nutrition and Dietetics, King's College London, United Kingdom.
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Plaschke J, Schwanebeck U, Pistorius S, Saeger HD, Schackert HK. Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and hereditary colorectal cancer with or without microsatellite instability. Cancer Lett 2003; 191:179-85. [PMID: 12618331 DOI: 10.1016/s0304-3835(02)00633-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate metabolism, which affects DNA synthesis and methylation. Low enzyme activity may reduce the capacity of DNA methylation, and possibly reduce uracil misincorporation into DNA, which can result in double strand breaks. Both processes may be critical for the oncogenic transformation of human cells. Two common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We performed estimations of the relative risk associated with these two polymorphisms in samples from 287 colorectal cancer patients, compared to 346 healthy controls. Relative risk were further determined for subpopulations of cancer patients having sporadic (n = 227) or suspected/verified hereditary disease (n = 60) and tumours exhibiting high-level microsatellite instability (n = 41) or not (n = 246). No significant differences for the relative risk of colorectal cancer were observed for the MTHFR genotypes either alone or in combination in the analysed cohorts, although the frequency of the 1298AA + AC genotypes was increased among the 60 cases with hereditary disease. Whereas our results do not support an association of high enzyme activity and increased risk of colorectal cancer in general, we can not exclude an association of patients with hereditary disease and the MTHFR 1298A --> C variant.
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Affiliation(s)
- Jens Plaschke
- Department of Surgical Research, Carl Gustav Carus Hospital, Dresden University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany.
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Marugame T, Tsuji E, Kiyohara C, Eguchi H, Oda T, Shinchi K, Kono S. Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas. Int J Epidemiol 2003; 32:64-6. [PMID: 12690011 DOI: 10.1093/ije/dyg004] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Folate intake may be related to decreased risk of colorectal cancer and adenomas. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate metabolism. We examined the relation between plasma folate status and colorectal adenomas with reference to effect modification by the genetic polymorphism (C677T) of MTHFR. METHODS Study subjects were middle-aged Japanese men: 177 cases of colorectal adenomas and 192 controls with normal total colonoscopy. Statistical adjustment was made for hospital, rank in the Self Defense Forces, alcohol use, smoking, and body mass index. RESULTS Plasma folate levels were slightly lower in adenoma cases than in controls. Adjusted odds ratio (OR) for high (>5.50 ng/ml) versus low plasma folate levels was 0.72 (95% CI: 0.46-1.14). As compared with subjects with the CC or CT genotype having low plasma folate levels, those with the TT genotype showed a decreased risk of colorectal adenomas when they had high levels of plasma folate (adjusted OR = 0.58, 95% CI: 0.21-1.61), and an increased risk when they had low folate levels (adjusted OR = 2.13, 95% CI: 0.82-5.54). There was no clear relation between plasma folate and colorectal adenomas among those with the CC or CT genotype. CONCLUSIONS The findings suggest an interaction between folate and the MTHFR genotype on colorectal adenomas.
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Affiliation(s)
- Tomomi Marugame
- Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
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30
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Teramukai S, Rohan T, Lee KY, Eguchi H, Oda T, Kono S. Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men. Jpn J Cancer Res 2002; 93:1187-94. [PMID: 12460458 PMCID: PMC5926902 DOI: 10.1111/j.1349-7006.2002.tb01222.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.
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Affiliation(s)
- Satoshi Teramukai
- Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
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Rampersaud GC, Bailey LB, Kauwell GPA. Relationship of folate to colorectal and cervical cancer: review and recommendations for practitioners. JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION 2002; 102:1273-82. [PMID: 12792626 DOI: 10.1016/s0002-8223(02)90281-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Evidence suggests that folate may play a role in cancer prevention. A plausible mechanism for prevention lies in the integral role that folate plays in deoxyribonucleic acid (DNA) synthesis and methylation. DNA methylation most likely regulates gene expression. Abnormal methylation, specifically hypomethylation, has been associated with tumorigenesis. The availability of methyl groups needed for adequate DNA methylation may be negatively influenced by low folate status, alcohol intake, or genetic polymorphisms that affect folate metabolism. Observational studies evaluating the association between folate and risk for colorectal and cervical cancers or precancerous conditions have produced conflicting results, and clinical trial data are needed to confirm a cause-and-effect relationship. However, several studies show interesting associations between cancer risk and factors that influence methyl group availability. Although data relating folate to cancer risk remain equivocal, when coupled with the other potential health benefits associated with folate, evidence supports recommending that people consume folate-rich foods such as fruits and vegetables. People consuming alcohol on a daily basis may especially benefit from additional folate in their diets.
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Affiliation(s)
- Gail C Rampersaud
- Food Science and Human Nutrition Department, Food and Environmental Toxicology Laboratory, University of Florida, Box 110720, Bldg 685, SW 23rd Drive, Gainesville, FL 32611-0720, USA
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32
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Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. AMERICAN JOURNAL OF PHARMACOGENOMICS : GENOMICS-RELATED RESEARCH IN DRUG DEVELOPMENT AND CLINICAL PRACTICE 2002; 1:189-201. [PMID: 12083967 DOI: 10.2165/00129785-200101030-00004] [Citation(s) in RCA: 146] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. Severe enzyme deficiency leads to hyperhomocysteinemia and homocystinuria, with altered folate distribution and a phenotype that is characterized by damage to the nervous and vascular systems. Two frequent polymorphisms in the human MTHFR gene confer moderate functional impairment of MTHFR activity for homozygous mutant individuals. The C to T change at nucleotide position 677, whose functional consequences are dependent on folate status, has been extensively studied for its clinical consequences. A second polymorphism, an A to C change at nucleotide position 1298, is not as well characterized. Still equivocal are associations between MTHFR polymorphisms and vascular arteriosclerotic or thrombotic disease. Neural tube defects and pregnancy complications appear to be linked to impaired MTHFR function. Colonic cancer and acute leukemia, however, appear to be less frequent in individuals homozygous for the 677T polymorphism.MTHFR polymorphisms influence the homocysteine-lowering effect of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. However, only preliminary evidence exists for gene-drug interactions. This review summarizes the biochemical basis and clinical evidence for interactions between MTHFR polymorphisms and several disease entities, as well as potential interactions with drug therapies. Future investigations of MTHFR in disease should consider the influence of other variants of functionally-related genes as well as the medication regimen of the patients. Animal models for genetic deficiencies in folate metabolism will likely play a greater role in our understanding of folate-dependent disorders.
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Affiliation(s)
- B Schwahn
- Departments of Pediatrics, Human Genetics and Biology, McGill University-Montreal Children's Hospital, Montreal, Quebec, Canada
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Abstract
Evidence emerging from many different types of experimental designs continues to support the concept that dietary habits and nutritional status play important roles in determining the risk of colorectal cancer. This field of investigation is nevertheless very confusing, particularly because longstanding hypotheses, such as the presumed protective effects of fruits, vegetables, and fiber, have recently been challenged by well-designed prospective trials. The search for individual components in the diet that convey protection continues: calcium, folate, selenium, and omega-3 fatty acids are the leading candidates in this regard. There is also growing interest in other plant-based compounds, so-called phytochemicals, although our understanding of their effects is quite rudimentary at present. Although the inconsistencies in this field make it tempting to minimize its import, there is little question that diet has a major impact on colorectal cancer risk; diligent attention to the rigorous conduct of studies and their interpretation will likely clarify these relationships over the next decade, much to the benefit of public health.
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Affiliation(s)
- Joel B Mason
- School of Medicine, Vitamins and Carcinogenesis Program, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.
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Little J, Sharp L. Colorectal neoplasia and genetic polymorphisms associated with folate metabolism. Eur J Cancer Prev 2002; 11:105-10. [PMID: 11917217 DOI: 10.1097/00008469-200202000-00016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- J Little
- Department of Medicine and Therapeutics, University of Aberdeen Medical School, Polwarth Building, Foresterhill, Aberdeen, Scotland, AB25 2ZD, UK.
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Shen H, Xu Y, Zheng Y, Qian Y, Yu R, Qin Y, Wang X, Spitz MR, Wei Q. Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study. Int J Cancer 2001; 95:332-6. [PMID: 11494235 DOI: 10.1002/1097-0215(20010920)95:5<332::aid-ijc1058>3.0.co;2-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Low dietary folate intake has been associated with increased risk of gastric cancer. The 5,10-methylenetetrahydrofolate reductase (MTHFR) involved in folate metabolism has 2 variants, C677T and A1298C, that result in decreased MTHFR activity and lower plasma folate levels. Therefore, we hypothesized that these 2 variants play a role in gastric carcinogenesis. We tested this hypothesis in a Chinese population-based case-control study of 187 histopathologically confirmed gastric cancer cases and 166 healthy controls frequency-matched by age (+/-5 years), gender and residential area. The 677TT genotype was associated with increased risk for gastric cancer [adjusted odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.00-3.48] compared to the 677CC genotype. This association was more pronounced for gastric cardia cancer (adjusted OR = 2.47, 95% CI = 1.14-5.32). However, no evidence was found for risk associated with the MTHFR A1298C polymorphism. Our findings support the hypothesis that MTHFR C677T variants contribute to gastric carcinogenesis, particularly in gastric cardia. Larger studies incorporating dietary folate intake and serum levels are needed to confirm our findings.
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Affiliation(s)
- H Shen
- Department of Epidemiology and Statistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
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Ryan BM, Weir DG. Relevance of folate metabolism in the pathogenesis of colorectal cancer. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2001; 138:164-76. [PMID: 11528369 DOI: 10.1067/mlc.2001.117161] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The purpose of this review is to outline the principal mechanisms involved in folate metabolism and how they may relate to the pathogenesis of colorectal cancer (CRC). In recent years, mild folate depletion (low normal level) has been associated with an increased risk of developing certain cancers, in particular colorectal neoplasia. The epidemiologic and mechanistic evidence linking folate deficiency with carcinogenesis is reviewed, with a particular emphasis on colorectal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is a critical folate metabolizing enzyme, and a functional polymorphic variant of this enzyme, the so-called thermolabile variant, caused by a C677T transition in the MTHFR gene, is common in the general population. This review critically examines the evidence that suggests that carriers of this C677T variant may be at increased risk of developing colorectal neoplasia. Although folate depletion may predispose to the initiation of the neoplastic process, folate supplementation, on the other hand, might potentiate the progression of an already established early neoplastic clone (eg, a colorectal adenoma). This could have potential public health implications, given an increasingly widespread policy of folate supplementation of food staples.
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Affiliation(s)
- B M Ryan
- Department of Clinical Medicine, St James's Hospital and Trinity College, Dublin, Ireland
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Crott JW, Mashiyama ST, Ames BN, Fenech MF. Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro. Carcinogenesis 2001; 22:1019-25. [PMID: 11408344 DOI: 10.1093/carcin/22.7.1019] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme which converts 5,10-methylene tetrahydrofolate (5,10-MnTHF) to 5-methyl tetrahydrofolate. A common C to T transition (C677T) in the MTHFR gene is reported to reduce the risk for colorectal cancer and acute lymphocytic leukemia in homozygotes (TTs). It is hypothesized that because TTs have reduced MTHFR activity, more 5,10-MnTHF is available to provide methyl groups for the conversion of uracil to thymidine. Folic acid deficiency causes the intracellular accumulation of dUMP and the subsequent incorporation of uracil into DNA. The removal of uracil from DNA may result in double-stranded DNA breaks, the accumulation of which is a putative risk factor for cancer. We tested whether human lymphocytes taken from TTs (n = 10) were more able to resist uracil incorporation into DNA than controls (n = 14 CCs and 6 CTs) when cultured in medium containing 12-120 nM folic acid for 9 days. DNA uracil content of these lymphocytes was measured by CG-MS. TTs and controls showed a dose-dependent increase in DNA uracil content during folic acid deficiency (P < 0.0001, R2 = 0.23 for TTs and P < 0.0001, R2 = 0.19 for controls). DNA uracil content was not different between the two groups at any of the folic acid concentrations (two-way ANOVA: media [folic acid], P < 0.0001; genotype, P = 0.4). The results show that, in this in vitro system, the MTHFR C677T polymorphism does not affect the cell's ability to resist uracil incorporation into DNA. Chromosome breakage, as measured by micronuclei, was also shown to correlate with folic acid concentration in a preliminary experiment (P < 0.0001). Although the results appear not to support the hypothesis that a reduced risk for certain cancers in TTs is due to diversion of folic acid to thymidine synthesis, differences between the in vivo and in vitro situation make this conclusion not definitive.
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Affiliation(s)
- J W Crott
- Department of Physiology, Adelaide University, SA 5005, Australia
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Mogk RL, Rothenmund H, Evans JA, Carson N, Dawson AJ. The frequency of the C677T substitution in the methylenetetrahydrofolate reductase gene in Manitoba. Clin Genet 2000; 58:406-8. [PMID: 11140843 DOI: 10.1034/j.1399-0004.2000.580513.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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