Journal of Neuro-Oncology

, Volume 105, Issue 3, pp 639–646 | Cite as

A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma

  • Jennifer Permuth-Wey
  • Reid C. Thompson
  • L. Burton Nabors
  • Jeffrey J. Olson
  • James E. Browning
  • Melissa H. Madden
  • Y. Ann Chen
  • Kathleen M. Egan
Clinical Study – Patient Study


MicroRNAs (miRNAs) are non-coding RNAs that function as post-transcriptional regulators of tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to carcinogenesis by altering expression of miRNAs and their targets. A G>C polymorphism (rs2910164) in the miR-146a precursor sequence leads to a functional change associated with the risk for numerous malignancies. A role for this SNP in glioma pathogenesis has not yet been examined. We investigated whether rs2910164 genotypes influence glioma risk and prognosis in a multi-center case–control study comprised of 593 Caucasian glioma cases and 614 community-based controls. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for rs2910164 genotypes according to case status. Cox proportional hazards regression modeling was used to estimate hazards ratios (HR) and 95% CIs according to genotype among glioblastomas, the most lethal glioma subtype. An increased glioma risk was observed among rs2910164 minor allele (C) carriers (per allele OR (95% CI) = 1.22 (1.01–1.46, p trend = 0.039)). The association was stronger among older subjects carrying at least one copy of the C allele (OR (95% CI) = 1.38 (1.04–1.83, P = 0.026). Mortality was increased among minor allele carriers (HR (95% CI) = 1.33 (1.03–1.72, P = 0.029)), with the association largely restricted to females (HR (95% CI) = 2.02 (1.28–3.17, P = 0.002)). We provide novel data suggesting rs2910164 genotype may contribute to glioma susceptibility and outcome. Future studies are warranted to replicate these findings and characterize mechanisms underlying these associations.


Genotype Glioma Susceptibility Single nucleotide polymorphism MicroRNA 



The authors wish to acknowledge the study participants without whom the research would not have been possible. We further wish to thank the clinicians and research staffs at participating medical centers for their contributions. Finally, we thank Ms. Anna Konidari and staff at the Center for Genome Technology at the Hussman Institute for Human Genomics, University of Miami for their expert technical assistance in genotyping. The project was supported by the National Institutes of Health (CA R01CA116174) and institutional funding provided by the Moffitt Cancer Center (Tampa, FL) and the Vanderbilt-Ingram Comprehensive Cancer Center (Nashville, TN).


  1. 1.
    American Cancer Society (2010) Cancer Facts and Figures 2010. American Cancer Society, AtlantaGoogle Scholar
  2. 2.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109PubMedCrossRefGoogle Scholar
  3. 3.
    Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, Kruchko C, McCarthy BJ, Rajaraman P, Schwartzbaum JA, Sadetzki S, Schlehofer B, Tihan T, Wiemels JL, Wrensch M, Buffler PA (2008) Brain tumor epidemiology: consensus from the brain tumor epidemiology consortium. Cancer 113:1953–1968PubMedCrossRefGoogle Scholar
  4. 4.
    Hemminki K, Li X (2003) Familial risks in nervous system tumors. Cancer Epidemiol Biomarkers Prev 12:1137–1142PubMedGoogle Scholar
  5. 5.
    Scheurer ME, Etzel CJ, Liu M, El-Zein R, Airewele GE, Malmer B, Aldape KD, Weinberg JS, Yung WK, Bondy ML (2007) Aggregation of cancer in first-degree relatives of patients with glioma. Cancer Epidemiol Biomarkers Prev 16:2491–2495PubMedCrossRefGoogle Scholar
  6. 6.
    Gu J, Liu Y, Kyritsis AP, Bondy ML (2009) Molecular epidemiology of primary brain tumors. Neurotherapeutics 6:427–435PubMedCrossRefGoogle Scholar
  7. 7.
    Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, Bergenheim AT, Feychting M, Lonn S, Ahlbom A, Schramm J, Linnebank M, Hemminki K, Kumar R, Hepworth SJ, Price A, Armstrong G, Liu Y, Gu X, Yu R, Lau C, Schoemaker M, Muir K, Swerdlow A, Lathrop M, Bondy M, Houlston RS (2009) Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41:899–904PubMedCrossRefGoogle Scholar
  8. 8.
    Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, Ballman KV, Berger M, Buckner JC, Chang S, Giannini C, Halder C, Kollmeyer TM, Kosel ML, LaChance DH, McCoy L, O’Neill BP, Patoka J, Pico AR, Prados M, Quesenberry C, Rice T, Rynearson AL, Smirnov I, Tihan T, Wiemels J, Yang P, Wiencke JK (2009) Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 41:905–908PubMedCrossRefGoogle Scholar
  9. 9.
    Egan KM, Thompson RC, Nabors LB, Olson JJ, Brat DJ, Larocca RV, Brem S, Moots PL, Madden MH, Browning JE, Ann Chen Y (2011) Cancer susceptibility variants and the risk of adult glioma in a US case-control study. J Neurooncol 1–8Google Scholar
  10. 10.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRefGoogle Scholar
  11. 11.
    Silber J, James CD, Hodgson JG (2009) microRNAs in gliomas: small regulators of a big problem. Neuromolecular Med 11:208–222PubMedCrossRefGoogle Scholar
  12. 12.
    Turner JD, Williamson R, Almefty KK, Nakaji P, Porter R, Tse V, Kalani MY (2010) The many roles of microRNAs in brain tumor biology. Neurosurg Focus 28: E3Google Scholar
  13. 13.
    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
  14. 14.
    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
  15. 15.
    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
  16. 16.
    Xu B, Feng NH, Li PC, Tao J, Wu D, Zhang ZD, Tong N, Wang JF, Song NH, Zhang W, Hua LX, Wu HF (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
  17. 17.
    Xu T, Zhu Y, Wei QK, Yuan Y, Zhou F, Ge YY, Yang JR, Su H, Zhuang SM (2008) A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis 29:2126–2131PubMedCrossRefGoogle Scholar
  18. 18.
    Guo H, Wang K, Xiong G, Hu H, Wang D, Xu X, Guan X, Yang K, Bai Y (2010) A functional varient in microRNA-146a is associated with risk of esophageal squamous cell carcinoma in Chinese Han. Fam CancerGoogle Scholar
  19. 19.
    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
  20. 20.
    Okubo M, Tahara T, Shibata T, Yamashita H, Nakamura M, Yoshioka D, Yonemura J, Kamiya Y, Ishizuka T, Nakagawa Y, Nagasaka M, Iwata M, Yamada H, Hirata I, Arisawa T (2010) Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis. J Clin Immunol 31(1):69–73PubMedCrossRefGoogle Scholar
  21. 21.
    Li L, Chen XP, Li YJ (2010) MicroRNA-146a and human disease. Scand J Immunol 71:227–231PubMedCrossRefGoogle Scholar
  22. 22.
    Barcellos-Hoff MH, Newcomb EW, Zagzag D, Narayana A (2009) Therapeutic targets in malignant glioblastoma microenvironment. Semin Radiat Oncol 19:163–170PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou M, Wiemels JL, Bracci PM, Wrensch MR, McCoy LS, Rice T, Sison JD, Patoka JS, Wiencke JK (2010) Circulating levels of the innate and humoral immune regulators CD14 and CD23 are associated with adult glioma. Cancer Res 70:7534–7542PubMedCrossRefGoogle Scholar
  24. 24.
    Kabat GC, Etgen AM, Rohan TE (2010) Do steroid hormones play a role in the etiology of glioma? Cancer Epidemiol Biomarkers Prev 19:2421–2427PubMedCrossRefGoogle Scholar
  25. 25.
    Lin SL, Chiang A, Chang D, Ying SY (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14:417–424PubMedCrossRefGoogle Scholar
  26. 26.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110PubMedCrossRefGoogle Scholar
  27. 27.
    Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486PubMedCrossRefGoogle Scholar
  28. 28.
    Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanisms of angiogenesis in gliomas. J Neurooncol 78:281–293PubMedCrossRefGoogle Scholar
  29. 29.
    Atkinson GP, Nozell SE, Benveniste ET (2010) NF-kappaB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother 10:575–586PubMedCrossRefGoogle Scholar
  30. 30.
    Jazdzewski K, Liyanarachchi S, Swierniak M, Pachucki J, Ringel MD, Jarzab B, de la Chapelle A (2009) Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc Natl Acad Sci USA 106:1502–1505PubMedCrossRefGoogle Scholar
  31. 31.
    Labbaye C, Spinello I, Quaranta MT, Pelosi E, Pasquini L, Petrucci E, Biffoni M, Nuzzolo ER, Billi M, Foa R, Brunetti E, Grignani F, Testa U, Peschle C (2008) A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis. Nat Cell Biol 10:788–801PubMedCrossRefGoogle Scholar
  32. 32.
    Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221–1232PubMedCrossRefGoogle Scholar
  33. 33.
    Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP (1998) CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol 69:99–104PubMedCrossRefGoogle Scholar
  34. 34.
    do Carmo A, Patricio I, Cruz MT, Carvalheiro H, Oliveira CR, Lopes MC (2010) CXCL12/CXCR4 promotes motility and proliferation of glioma cells. Cancer Biol Ther 9:56–65PubMedCrossRefGoogle Scholar
  35. 35.
    Esencay M, Newcomb EW, Zagzag D (2010) HGF upregulates CXCR4 expression in gliomas via NF-kappaB: implications for glioma cell migration. J Neurooncol 99:33–40PubMedCrossRefGoogle Scholar
  36. 36.
    Ehtesham M, Winston JA, Kabos P, Thompson RC (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25:2801–2806PubMedCrossRefGoogle Scholar
  37. 37.
    Dou T, Wu Q, Chen X, Ribas J, Ni X, Tang C, Huang F, Zhou L, Lu D (2010) A polymorphism of microRNA196a genome region was associated with decreased risk of glioma in Chinese population. J Cancer Res Clin Oncol 136(12):1853–1859PubMedCrossRefGoogle Scholar
  38. 38.
    Hu Z, Chen J, Tian T, Zhou X, Gu H, Xu L, Zeng Y, Miao R, Jin G, Ma H, Chen Y, Shen H (2008) Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest 118:2600–2608PubMedCrossRefGoogle Scholar
  39. 39.
    Hu Z, Liang J, Wang Z, Tian T, Zhou X, Chen J, Miao R, Wang Y, Wang X, Shen H (2009) Common genetic variants in pre-microRNAs were associated with increased risk of breast cancer in Chinese women. Hum Mutat 30:79–84PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Jennifer Permuth-Wey
    • 1
  • Reid C. Thompson
    • 2
  • L. Burton Nabors
    • 3
  • Jeffrey J. Olson
    • 4
  • James E. Browning
    • 1
  • Melissa H. Madden
    • 1
  • Y. Ann Chen
    • 5
  • Kathleen M. Egan
    • 1
  1. 1.Department of Cancer Epidemiology, Division of Population SciencesH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Department of Neurological SurgeryVanderbilt University Medical CenterNashvilleUSA
  3. 3.Neuro-oncology ProgramUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of NeurosurgeryEmory University School of MedicineAtlantaUSA
  5. 5.Department of BiostatisticsH. Lee Moffitt Cancer Center & Research InstituteTampaUSA

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