Association of MTHFR gene polymorphisms with pancreatic cancer: meta-analysis of 17 case–control studies

  • Fangfang Nie
  • Mingli Yu
  • Kaili Zhang
  • Luping Yang
  • Qian Zhang
  • Shan Liu
  • Mengwei Liu
  • Mengke Shang
  • Fanxin Zeng
  • Wanyang LiuEmail author
Original Article



Pancreatic cancer (PC) is a seriously malignant tumor with a low 5-year survival rate. The relationship between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and PC has been reported by several studies. However, the results were controversial. Thus, we conducted a meta-analysis to summarize available data on MTHFR gene and PC.


We searched PubMed, Embase, Web of Science, Wanfang, CNKI databases prior to July 2019. Data were analyzed by RevMan 5.3 and STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Subgroup analysis, sensitivity analysis and assessment of publication bias were performed in this study.


Ten articles with 17 reports (10 for C677T, 7 for A1298C) were eligible for inclusion in the meta-analysis (1864 cases and 3165 controls for C677T, and 1488 cases and 1946 controls for A1298C). Our meta-analysis detected that C677T was associated with PC for three genetic models (allele model: OR = 1.24, 95% CI: 1.00–1.53, P = 0.047; recessive model: OR = 1.39, 95% CI: 1.04–1.86, P = 0.027; homozygous model: OR = 1.60, 95% CI: 1.04–2.45, P = 0.034). In the stratified analyses according to ethnicity, source of controls and genotyping method, significant association was observed in genotyping method subgroup. For the A1298C polymorphism, no significant association was observed either in overall analysis or in subgroup analysis under all genetic models.


MTHFR gene C677T rather than A1298C polymorphism may be associated with PC. Larger sample size studies should be performed to find the association between MTHFR gene and PC.


MTHFR gene Meta-analysis Pancreatic cancer Polymorphism 



This work was supported by the National Natural Science Foundation of China (Grant No. 81573240). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

All the authors declare no conflict of interest.

Ethical approval

This meta-analysis has no human or animal participants.

Informed consent

Formal consent is not required for this type of study.


  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rahib L, Smith BD, Aizenberg R et al (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Farthing M, Roberts SE, Samuel DG et al (2014) Survey of digestive health across Europe: final report. Part 1: The burden of gastrointestinal diseases and the organisation and delivery of gastroenterology services across Europe. United European Gastroenterol J 2:539–543PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Carrato A, Falcone A, Ducreux M et al (2015) A systematic review of the burden of pancreatic cancer in europe: real-world impact on survival, quality of life and costs. J Gastrointest Cancer 46:201–211PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lucas AL, Malvezzi M, Carioli G et al (2016) Global trends in pancreatic cancer mortality from 1980 through 2013 and predictions for 2017. Clin Gastroenterol Hepatol 14:1452.e4–1462.e4CrossRefGoogle Scholar
  6. 6.
    Parkin DM, Boyd L, Walker LC (2011) The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br J Cancer 105:S77–S81PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617CrossRefGoogle Scholar
  8. 8.
    Ezzati M, Henley SJ, Lopez AD et al (2005) Role of smoking in global and regional cancer epidemiology: current patterns and data needs. Int J Cancer 116:963–971PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Willett WC (2000) Diet and cancer. Oncologist 5:393–404PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Anand P, Kunnumakkara AB, Sundaram C et al (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Chittiboyina S, Chen ZX, Chiorean EG et al (2018) The role of the folate pathway in pancreatic cancer risk. PLoS One 13:e0193298PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Kim YI, Pogribny IP, Basnakian AG et al (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am J of Clin Nutr 65:46–52CrossRefGoogle Scholar
  13. 13.
    Sibani S, Melnyk S, Pogribny IP et al (2002) Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis 23:61–65PubMedCrossRefGoogle Scholar
  14. 14.
    Zweier C, Temple IK, Beemer F et al (2003) Characterisation of deletions of the ZFHX1B region and genotype-phenotype analysis in Mowat–Wilson syndrome. J Med Genet 40:601–605PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Yang BY, Liu YY, Li YF et al (2013) Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: findings from 15357 adults of Han nationality. PLoS One 8:e57917PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Zhong R, Chen QL, Zhang XY et al (2019) Association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and lung cancer risk in Chinese people: An updated meta-analysis. Medicine (Baltimore) 98:e16037CrossRefGoogle Scholar
  17. 17.
    Xu LY, Qin ZQ, Wang F et al (2017) Methylenetetrahydrofolate reductase C677T polymorphism and colorectal cancer susceptibility: a meta-analysis. Biosci Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wei LS, Niu FL, Wu JM et al (2019) Association study between genetic polymorphisms in folate metabolism and gastric cancer susceptibility in Chinese Han population: a case-control study. Mol Genet Genomic Med 7:e633PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Guo SQ, Jiang XK, Chen XB et al (2015) The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: evidence from 23 case-control studies. Gene 565:90–95PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hajiesmaeil M, Tafvizi F, Sarmadi S (2016) The effect of methylenetetrahydrofolate reductase polymorphisms on susceptibility to human papilloma virus infection and cervical cancer. Infect Genet Evol 46:1–6PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Liu W, Li Y, Li R et al (2016) Association of Mthfr A1298c polymorphism with breast cancer and/or ovarian cancer risk: an updated meta-analysis. Afr J Tradit Complement Altern Med 13:72–86PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Chen PL, Li WT, Wang J et al (2015) Association between MTHFR gene polymorphisms (C677T, A1298C) and genetic susceptibility to prostate cancer: a meta-analysis. Genet Mol Res 14:19191–19202PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Zhu XL, Liu ZZ, Yan SX et al (2016) Association between the MTHFR A1298C polymorphism and risk of cancer: evidence from 265 case-control studies. Mol Genet Genomics 291:51–63PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Wells GA, Shea B, Connell DO’ et al (2012) The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta analyses.
  25. 25.
    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Begg CB, Mazumdar M (1995) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefGoogle Scholar
  27. 27.
    Kiene H, Kienle GS, von Schön-Angerer T (2006) Bias in meta-analysis. Homeopathy 95:54PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Li DH, Ahmed M, Li YN et al (2005) 5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer. Cancer Epidemiol Biomark Prev 14:1470–1476CrossRefGoogle Scholar
  29. 29.
    Suzuki T, Matsuo K, Sawaki A et al (2008) Alcohol drinking and one-carbon metabolism-related gene polymorphisms on pancreatic cancer risk. Cancer Epidemiol Biomark Prev 17:2742–2747CrossRefGoogle Scholar
  30. 30.
    Nakao H, Wakai K, Ishii N et al (2016) Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects. BMC Gastroenterol 16:83PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Mazzuca F, Borro M, Botticelli A et al (2015) Effect of MTHFR polymorphisms on gastrointestinal cancer risk in Italy. World J Oncol 6:394–397PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wang L, Miao XP, Tan W et al (2005) Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer. Clin Gastroenterol Hepatol 3:743–751PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Nisevic I, Dinic J, Nikolic A et al (2008) MTHFR C677T polymorphism in chronic pancreatitis and pancreatic adenocarcinoma. Cell Biochem Funct 26:659–663PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Matsubayashi H, Skinner HG, Iacobuzio-Donahue C et al (2005) Pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypes. Clin Gastroenterol Hepatol 3:752–760PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Wang L, Lin DX, Lu XH et al (2006) Study on the relations between genetic polymorphisms in methylenetetrahydrofolate reductase, methionine synthase and the risk of pancreatic cancer. Chinese J Epidemiol 27:50–54Google Scholar
  36. 36.
    Yang XO (2009) The study of the relevant SNPs on the risk of pancreatic cancer and high risk population. Dissertation, Peking Union Medical CollegeGoogle Scholar
  37. 37.
    Weisberg I, Tran P, Christensen B et al (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172PubMedCrossRefGoogle Scholar
  38. 38.
    Liu XM, Liu FH, Tang Y et al (2012) MTHFR C677T polymorphism and pancreatic cancer risk: a meta-analysis. Asian Pac J Cancer Prev 13:3763–3766PubMedCrossRefGoogle Scholar
  39. 39.
    Tu YL, Wang SB, Tan XL et al (2012) MTHFR gene polymorphisms are not involved in pancreatic cancer risk: a meta-analysis. Asian Pac J Cancer Prev 13:4627–4630PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Li L, Wu SD, Wang JY et al (2012) MTHFR polymorphisms and pancreatic cancer risk: lack of evidence from a meta-analysis. Asian Pac J Cancer Prev 13:2249–2252PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Larsson SC, Giovannucci E, Wolk A et al (2006) Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology 131:1271–1283PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Heller T, Kirchheiner J, Armstrong VW et al (2006) AmpliChip CYP450 GeneChip: a new gene chip that allows rapid and accurate CYP2D6 genotyping. Ther Drug Monit 28:673–677PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Li L, Li CJ, Zhang YJ et al (2011) Simultaneous detection of CYP3A5 and MDR1 polymorphisms based on the SNaPshot assay. Clin Biochem 44:418–422PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Zhou C, Ni J, Zhao Y et al (2006) Rapid detection of epidermal growth factor receptor mutations in non-small cell lung cancer using real-time polymerase chain reaction with TaqMan-MGB probes. Cancer J (Sudbury, Mass) 12:33–39CrossRefGoogle Scholar
  45. 45.
    Li TD, Yang HW, Wang P et al (2019) Coffee consumption and risk of pancreatic cancer: a systematic review and dose-response meta-analysis. Int J Food Sci Nutr 70:519–529PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Milenal I, Irena I (2016) Epidemiology of pancreatic cancer. World J Gastroenterol 22:9694–9705CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  1. 1.Department of Nutrition and Food Hygiene, School of Public HealthChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Social Medicine, School of Public HealthChina Medical UniversityShenyangChina

Personalised recommendations