A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma
- 274 Downloads
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.
KeywordsGenotype 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.American Cancer Society (2010) Cancer Facts and Figures 2010. American Cancer Society, AtlantaGoogle Scholar
- 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
- 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.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.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
- 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
- 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
- 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
- 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