- Volume 15 Issue 19
DOI QR Code
5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Colon Cancer Risk: a Meta-analysis
- Fang, Xin-Yu (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Xu, Wang-Dong (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Huang, Qian (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Yang, Xiao-Ke (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Liu, Yan-Yan (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Leng, Rui-Xue (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Pan, Hai-Feng (Epidemiology and Statistics, School of Public Health, Anhui Medical University) ;
- Ye, Dong-Qing (Epidemiology and Statistics, School of Public Health, Anhui Medical University)
- Published : 2014.10.23
Previous studies investigating the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and colon cancer risk have generated conflicting results. The aim of our meta-analysis was to clarify the precise association. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CI) were used to estimate the strength of the association. In this meta-analysis, a total of 13 articles, involving 5,386 cases and 8,017 controls met the inclusion criteria. Overall, a significant association was found between colon cancer risk and the MTHFR C667 polymorphism (TT vs CC+CT: OR=0.79; 95%CI=0.65-0.96; p=0.017). Stratification by ethnicity revealed that MTHFRC667 was associated with colon cancer risk in the non-Asian group (TT vs CC+CT:OR=0.77, 95%CI=0.68-0.89, p=0.000; TT vs CC: OR=0.84, 95%CI=0.73-0.97, p=0.016). Stratification by source of control indicated that MTHFR C667 also correlated with colon cancer risk in the population-based subgroup (TT vs CC: OR=0.85, 95%CI=0.74-0.97, p=0.017; TT vs CC+CT: OR=0.78, 95%CI=0.68-0.89, p=0.000) and hospital-based subgroup (TT vs CC+CT: OR=0.65, 95%CI=0.49-0.86, p=0.003). However, risk was significantly increased for MTHFR A1298C polymorphisms and colon cancer risk in hospital-based studies (C vs A: OR=1.52, 95%CI=1.26-1.83, p=0.000; CC+AC vs AA: OR=1.93, 95%CI=1.47-2.49, p=0.000) but reduced in population-based studies (CC vs AA: OR=0.83, 95%CI=0.70-0.99, p=0.042). In conclusion, the results of our meta-analysis suggest that the MTHFR C667 polymorphism is associated with reduced colon cancer risk, especially for non-Asian populations.
5, 10-methylenetetrahydrofolate reductase;polymorphisms;colon cancer;meta-analysis;non-Asians
- Chen J, Giovannucci E, Kelsey K, et al (1996). A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res, 56, 4862-4.
- Blount BC, Ames BN (1995). DNA damage in folate deficiency. Baillieres Clin Haematol, 8, 461-78. https://doi.org/10.1016/S0950-3536(05)80216-1
- Boutron-Ruault MC, Senesse P, Meance S, et al (2001). Energy intake, body mass index, physical activity, and the colorectal adenoma-carcinoma sequence. Nutr Cancer, 39, 50-7. https://doi.org/10.1207/S15327914nc391_7
- Cao HX, Gao CM, Takezaki T, et al (2008). Genetic polymorphisms of methylenetetrahydrofolate reductase and susceptibility to colorectal cancer. Asian Pac J Cancer Prev, 9, 203-8.
- Chen J, Huang ZJ, Duan YQ, et al (2012). Aberrant DNA methylation of P16, MGMT, and hMLH1 genes in combination with MTHFR C677T genetic polymorphism and folate intake in esophageal squamous cell carcinoma. Asian Pac J Cancer Prev, 13, 5303-6. https://doi.org/10.7314/APJCP.2012.13.10.5303
- Choi SW, Mason JB (2000). Folate and carcinogenesis: an integrated scheme. J Nutr, 130, 129-32.
- Curtin K, Slattery ML, Ulrich CM, et al (2007). Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis, 28, 1672-9. https://doi.org/10.1093/carcin/bgm089
- Egger M, Davey Smith G, Schneider M, et al (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34. https://doi.org/10.1136/bmj.315.7109.629
- Frosst P, Blom HJ, Milos R, et al (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet, 10, 111-3. https://doi.org/10.1038/ng0595-111
- Gao S, Ding LH, Wang JW, et al (2013). Diet folate, DNA methylation and polymorphisms in methylenetetrahydrofolate reductase in association with the susceptibility to gastric cancer. Asian Pac J Cancer Prev, 14, 299-302. https://doi.org/10.7314/APJCP.2013.14.1.299
- Jiang Q, Chen K, Ma X, et al (2005). Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer. Cancer Detect Prev, 29, 146-54. https://doi.org/10.1016/j.cdp.2004.11.004
- Giovannucci E (2001). An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev, 10, 725-31.
- Goyette P, Pai A, Milos R, et al (1998). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome, 9, 652-6. https://doi.org/10.1007/s003359900838
- Higgins JP, Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58. https://doi.org/10.1002/sim.1186
- Jokic M, Brcic-Kostic K, Stefulj J, et al (2011). Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer. DNA Cell Biol, 30, 771-6. https://doi.org/10.1089/dna.2010.1189
- Keku T, Millikan R, Worley K, et al (2002). 5, 10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev, 11, 1611-21.
- Kim DH, Ahn YO, Lee BH, et al (2004). Methylenetetrahydrofolate reductase polymorphism, alcohol intake, and risks of colon and rectal cancers in Korea. Cancer Lett, 216, 199-205. https://doi.org/10.1016/j.canlet.2004.08.014
- Kim J, Cho YA, Kim DH, et al (2012). Dietary intake of folate and alcohol, MTHFR C677T polymorphism, and colorectal cancer risk in Korea. Am J Clin Nutr, 95, 405-12. https://doi.org/10.3945/ajcn.111.020255
- Komlosi V, Hitre E, Pap E, et al (2010). SHMT1 1420 and MTHFR 677 variants are associated with rectal but not colon cancer. BMC Cancer, 10, 525. https://doi.org/10.1186/1471-2407-10-525
- Le Marchand L, Donlon T, Hankin JH, et al (2002). B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control, 13, 239-48. https://doi.org/10.1023/A:1015057614870
- Potter JD, Slattery ML, Bostick RM, et al (1993). Colon cancer: a review of the epidemiology. Epidemiol Rev, 15, 499-545.
- Liang TJ, Liu H, Zhao XQ, et al (2014). Quantitative assessment of the association between MTHFR rs1801131 polymorphism and risk of liver cancer. Tumour Biol, 35, 339-43. https://doi.org/10.1007/s13277-013-1046-y
- Lv L, Wang P, Sun B, et al (2014). The polymorphism of methylenetetrahydrofolate reductase C677T but not A1298C contributes to gastric cancer. Tumour Biol, 35, 227-37. https://doi.org/10.1007/s13277-013-1028-0
- Ma J, Stampfer MJ, Giovannucci E, et al (1997). Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res, 57, 1098-102.
- Promthet SS, Pientong C, Ekalaksananan T, et al (2010). Risk factors for colon cancer in Northeastern Thailand: interaction of MTHFR codon 677 and 1298 genotypes with environmental factors. J Epidemiol, 20, 329-38. https://doi.org/10.2188/jea.JE20090140
- Qu HH, Cui LH, Wang K, et al (2013). The methylenetetrahydrofolate reductase C677T polymorphism influences risk of esophageal cancer in Chinese. Asian Pac J Cancer Prev, 14, 3163-8. https://doi.org/10.7314/APJCP.2013.14.5.3163
- Rai PS, Pai GC, Alvares JF, et al (2014). Intraindividual somatic variations in MTHFR gene polymorphisms in relation to colon cancer. Pharmacogenomics, 15, 349-59. https://doi.org/10.2217/pgs.14.4
- Saberi S, Zendehdel K, Jahangiri S, et al (2012). Impact of methylenetetrahydrofolate reductase C677T polymorphism on the risk of gastric cancer and its interaction with Helicobacter pylori infection. Iran Biomed J, 16, 179-84.
- Safarinejad MR, Shafiei N, Safarinejad S (2012). Methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C and G1793A polymorphisms: association with risk for clear cell renal cell carcinoma and tumour behaviour in men. Clin Oncol, 24, 269-81. https://doi.org/10.1016/j.clon.2011.03.005
- Tan X, Wang YY, Dai L, et al (2013). Genetic polymorphism of MTHFR A1298C and esophageal cancer susceptibility: a meta-analysis. Asian Pac J Cancer Prev, 14, 1951-5. https://doi.org/10.7314/APJCP.2013.14.3.1951
- Slattery ML, Potter JD, Samowitz W, et al (1999). Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev, 8, 513-8.
- Stern LL, Mason JB, Selhub J, et al (2000). Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev, 9, 849-53.
- Taioli E, Garza MA, Ahn YO, et al (2009). Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review. Am J Epidemiol, 170, 1207-21. https://doi.org/10.1093/aje/kwp275
- Toffoli G, Gafa R, Russo A, et al (2003). Methylenetetrahydrofolate reductase 677 C-->T polymorphism and risk of proximal colon cancer in north Italy. Clin Cancer Res, 9, 743-8.
- Ueland PM, Hustad S, Schneede J, et al (2001). Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci, 22, 195-201. https://doi.org/10.1016/S0165-6147(00)01675-8
- Wang J, Gajalakshmi V, Jiang J, et al (2006). Associations between 5, 10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case-control study in an Indian population. Int J Cancer, 118, 991-7. https://doi.org/10.1002/ijc.21438
- Xiong HL, Liu XQ, Sun AH, et al (2013). Aberrant DNA methylation of P16, MGMT, hMLH1 and hMSH2 genes in combination with the MTHFR C677T genetic polymorphism in gastric cancer. Asian Pac J Cancer Prev, 14, 3139-42. https://doi.org/10.7314/APJCP.2013.14.5.3139
- Prognostic Factors and the Role of Adjuvant Chemotherapy in Post-curative Surgery for Dukes B and C Colon Cancers and Survival Outcomes: a Malaysian Experience vol.16, pp.6, 2015, https://doi.org/10.7314/APJCP.2015.16.6.2237
- rs1801133 polymorphism and susceptibility to colorectal cancer in Iranian population: evidence of a case–control study and meta-analysis vol.17, pp.17, 2016, https://doi.org/10.2217/pgs-2016-0048
- Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis vol.37, pp.6, 2017, https://doi.org/10.1042/BSR20170917
- methylation in colorectal cancer pp.1750-192X, 2018, https://doi.org/10.2217/epi-2018-0030