Archives of Toxicology

, Volume 87, Issue 5, pp 825–833

A genetic variant in miR-146a modifies colorectal cancer susceptibility in a Chinese population



MicroRNAs (miRNAs) are a family of endogenous, small, noncoding RNA molecules that involved in a wide range of biological processes including differentiation, proliferation, and apoptosis. A polymorphism G>C (rs2910164) is located in the stem region opposite to the mature miR-146a sequence. In our study, we investigated whether rs2910164 is associated with the risk of colorectal cancer (CRC) in a Chinese population. We genotyped the rs2910164 polymorphism using TaqMan method and evaluated the association with CRC risk in a case–control study, including 1,147 CRC patients and 1,203 cancer-free controls. Logistic regression models were used to assess the genetic effects on the development of CRC. Overall, we found that rs2910164 was significantly associated with the reduced CRC risk [GC/CC versus GG: adjusted odds ratio (OR) = 0.78, 95 % confidence intervals (CIs) = 0.66–0.93]. In the stratification analysis, this decreased risk was also pronounced among non-smokers (0.75, 0.61–0.93), non-drinkers (0.77, 0.63–0.94), and no family history of cancer (0.79, 0.65–0.95). Furthermore, GC/CC genotypes were associated with reduced CRC susceptibility in intermediate differentiated CRC (0.75, 0.62–0.90), and similar effect was observed in patients with the advanced stage tumor (Dukes C and D) (0.76, 0.61–0.93). In conclusion, our results suggest that miR-146a rs2910164 may contribute to the susceptibility to CRC in a Chinese population. Further larger population-based prospective and functional studies are needed to validate our findings.


miR-146a Polymorphism Colorectal cancer Genetic susceptibility 


  1. Akkiz H, Bayram S, Bekar A, Akgollu E, Uskudar O, Sandikci M (2011) No association of pre-microRNA-146a rs2910164 polymorphism and risk of hepatocellular carcinoma development in Turkish population: a case-control study. Gene 486:104–109PubMedCrossRefGoogle Scholar
  2. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  3. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101PubMedCrossRefGoogle Scholar
  4. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRefGoogle Scholar
  5. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655PubMedCrossRefGoogle Scholar
  6. Catucci I, Yang R, Verderio P et al (2010) Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases. Hum Mutat 31:E1052–E1057PubMedCrossRefGoogle Scholar
  7. Center MM, Jemal A, Smith RA, Ward E (2009) Worldwide variations in colorectal cancer. CA Cancer J Clin 59:366–378PubMedCrossRefGoogle Scholar
  8. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  9. Duan R, Pak C, Jin P (2007) Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16:1124–1131PubMedCrossRefGoogle Scholar
  10. Dykxhoorn DM (2010) MicroRNAs and metastasis: little RNAs go a long way. Cancer Res 70:6401–6406PubMedCrossRefGoogle Scholar
  11. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCrossRefGoogle Scholar
  12. Ferrari P, Jenab M, Norat T et al (2007) Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 121:2065–2072PubMedCrossRefGoogle Scholar
  13. George GP, Gangwar R, Mandal RK, Sankhwar SN, Mittal RD (2011) Genetic variation in microRNA genes and prostate cancer risk in North Indian population. Mol Biol Rep 38:1609–1615PubMedCrossRefGoogle Scholar
  14. Gottwein E, Cai X, Cullen BR (2006) A novel assay for viral microRNA function identifies a single nucleotide polymorphism that affects Drosha processing. J Virol 80:5321–5326PubMedCrossRefGoogle Scholar
  15. Guo H, Wang K, Xiong G et al (2010) A functional variant in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han. Fam Cancer 9:599–603PubMedCrossRefGoogle Scholar
  16. Hezova R, Kovarikova A, Bienertova-Vasku J et al (2012) Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World J Gastroenterol 18:2827–2831PubMedCrossRefGoogle Scholar
  17. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRefGoogle Scholar
  18. Hishida A, Matsuo K, Goto Y, Naito M, Wakai K, Tajima K, Hamajima N (2011) Combined effect of miR-146a rs2910164 G/C polymorphism and Toll-like receptor 4 +3725 G/C polymorphism on the risk of severe gastric atrophy in Japanese. Dig Dis Sci 56:1131–1137PubMedCrossRefGoogle Scholar
  19. Hoffman AE, Zheng T, Yi C et al (2009) microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis. Cancer Res 69:5970–5977PubMedCrossRefGoogle Scholar
  20. Horikawa Y, Wood CG, Yang H et al (2008) Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma. Clin Cancer Res 14:7956–7962PubMedCrossRefGoogle Scholar
  21. Hu Z, Liang J, Wang Z et al (2008) Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat 30:79–84CrossRefGoogle Scholar
  22. Iwai N, Naraba H (2005) Polymorphisms in human pre-miRNAs. Biochem Biophys Res Commun 331:1439–1444PubMedCrossRefGoogle Scholar
  23. Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A (2008) Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA 105:7269–7274PubMedCrossRefGoogle Scholar
  24. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRefGoogle Scholar
  25. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39:673–677PubMedCrossRefGoogle Scholar
  26. Lian H, Wang L, Zhang J (2012) Increased risk of breast cancer associated with CC genotype of Has-miR-146a Rs2910164 polymorphism in Europeans. PLoS ONE 7:e31615PubMedCrossRefGoogle Scholar
  27. Liu Z, Li G, Wei S, Niu J, El-Naggar AK, Sturgis EM, Wei Q (2010) Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck. Cancer 116:4753–4760PubMedCrossRefGoogle Scholar
  28. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedCrossRefGoogle Scholar
  29. Lu LF, Boldin MP, Chaudhry A et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929PubMedCrossRefGoogle Scholar
  30. Lung RW, Wang X, Tong JH et al. (2012) A single nucleotide polymorphism in microRNA-146a is associated with the risk for nasopharyngeal carcinoma. Mol Carcinog. doi:10.1002/mc.21937
  31. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748PubMedGoogle Scholar
  32. Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460PubMedCrossRefGoogle Scholar
  33. Min KT, Kim JW, Jeon YJ, Jang MJ, Chong SY, Oh D, Kim NK (2011) Association of the miR-146aC>G, 149C>T, 196a2C>T, and 499A>G polymorphisms with colorectal cancer in the Korean population. Mol Carcinog Suppl 1:E65–E73. doi:10.1002/mc.21849
  34. Mittal RD, Gangwar R, George GP, Mittal T, Kapoor R (2011) Investigative role of pre-microRNAs in bladder cancer patients: a case-control study in North India. DNA Cell Biol 30:401–406PubMedCrossRefGoogle Scholar
  35. Ng EK, Chong WW, Jin H et al (2009) Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58:1375–1381PubMedCrossRefGoogle Scholar
  36. Okubo M, Tahara T, Shibata T et al (2010) Association between common genetic variants in pre-microRNAs and gastric cancer risk in Japanese population. Helicobacter 15:524–531PubMedCrossRefGoogle Scholar
  37. Paik JH, Jang JY, Jeon YK, Kim WY, Kim TM, Heo DS, Kim CW (2011) MicroRNA-146a downregulates NFkappaB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. Clin Cancer Res 17:4761–4771PubMedCrossRefGoogle Scholar
  38. Pastrello C, Polesel J, Della Puppa L, Viel A, Maestro R (2010) Association between hsa-mir-146a genotype and tumor age-of-onset in BRCA1/BRCA2-negative familial breast and ovarian cancer patients. Carcinogenesis 31:2124–2126PubMedCrossRefGoogle Scholar
  39. Permuth-Wey J, Thompson RC, Burton Nabors L et al (2011) A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma. J Neurooncol 105:639–646PubMedCrossRefGoogle Scholar
  40. Schottenfeld D, Fraumeni JF (2006) Cancer epidemiology and prevention. Oxford University Press, USACrossRefGoogle Scholar
  41. Shen J, Ambrosone CB, DiCioccio RA, Odunsi K, Lele SB, Zhao H (2008) A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis. Carcinogenesis 29:1963–1966PubMedCrossRefGoogle Scholar
  42. Shimizu N, Nagata C, Shimizu H, Kametani M, Takeyama N, Ohnuma T, Matsushita S (2003) Height, weight, and alcohol consumption in relation to the risk of colorectal cancer in Japan: a prospective study. Br J Cancer 88:1038–1043PubMedCrossRefGoogle Scholar
  43. Srivastava K, Srivastava A, Mittal B (2010) Common genetic variants in pre-microRNAs and risk of gallbladder cancer in North Indian population. J Hum Genet 55:495–499PubMedCrossRefGoogle Scholar
  44. Terry P, Ekbom A, Lichtenstein P, Feychting M, Wolk A (2001) Long-term tobacco smoking and colorectal cancer in a prospective cohort study. Int J Cancer 91:585–587PubMedCrossRefGoogle Scholar
  45. Tian T, Shu Y, Chen J et al (2009) A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev 18:1183–1187PubMedCrossRefGoogle Scholar
  46. Wang J, Bi J, Liu X, Li K, Di J, Wang B (2012a) Has-miR-146a polymorphism (rs2910164) and cancer risk: a meta-analysis of 19 case-control studies. Mol Biol Rep 39:4571–4579PubMedCrossRefGoogle Scholar
  47. Wang M, Chu H, Li P et al (2012b) Genetic variants in microRNAs predict bladder cancer risk and recurrence. Cancer Res 72:6173–6182Google Scholar
  48. Xiang Y, Fan S, Cao J, Huang S, Zhang LP (2012) Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep 39:7019–7023PubMedCrossRefGoogle Scholar
  49. Xu T, Zhu Y, Wei QK et al (2008) A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis 29:2126–2131PubMedCrossRefGoogle Scholar
  50. Xu B, Feng NH, Li PC et al (2010) A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate 70:467–472PubMedCrossRefGoogle Scholar
  51. Yang H, Dinney CP, Ye Y, Zhu Y, Grossman HB, Wu X (2008) Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. Cancer Res 68:2530–2537PubMedCrossRefGoogle Scholar
  52. Yue C, Wang M, Ding B et al (2011) Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population. Gynecol Oncol 122:33–37PubMedCrossRefGoogle Scholar
  53. Zeng Y, Sun QM, Liu NN, Dong GH, Chen J, Yang L, Wang B (2010) Correlation between pre-miR-146a C/G polymorphism and gastric cancer risk in Chinese population. World J Gastroenterol 16:3578–3583PubMedCrossRefGoogle Scholar
  54. Zhou B, Wang K, Wang Y, Xi M, Zhang Z, Song Y, Zhang L (2011) Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma. Mol Carcinog 50:499–505PubMedCrossRefGoogle Scholar
  55. Zhou F, Zhu H, Luo D et al (2012a) A functional polymorphism in Pre-miR-146a is associated with susceptibility to gastric cancer in a Chinese population. DNA Cell Biol 31:1290–1295PubMedCrossRefGoogle Scholar
  56. Zhou J, Lv R, Song X et al (2012b) Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population. DNA Cell Biol 31:524–530PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Lan Ma
    • 1
    • 2
  • Lingjun Zhu
    • 3
  • Dongying Gu
    • 4
  • Haiyan Chu
    • 2
  • Na Tong
    • 2
  • Jinfei Chen
    • 4
  • Zhengdong Zhang
    • 2
  • Meilin Wang
    • 1
    • 2
  1. 1.Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public HealthNanjing Medical UniversityNanjingChina
  2. 2.Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, School of Public HealthNanjing Medical UniversityNanjingChina
  3. 3.Department of OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  4. 4.Department of Oncology, Nanjing First HospitalNanjing Medical UniversityNanjingChina

Personalised recommendations