Associations of miR‑146aC>G, miR‑149C>T, miR‑196a2C>T and miR‑499A>G polymorphisms with brain tumors
- Authors:
- Published online on: July 11, 2018 https://doi.org/10.3892/or.2018.6557
- Pages: 1813-1823
Abstract
Introduction
MicroRNAs (miRNAs/miRs) regulate mRNA expression through RNA interference and are known to be associated with various diseases (1–3). Abnormal miRNA expression is a well-known and crucial factor that is associated with the initiation and progression of various tumors, including brain tumors and breast cancer (1,4,5). The term brain tumor describes an inhomogeneous collection of tumors of the brain, which can be either malignant or benign and either originate in the central nervous system or represent metastases from other tumors (4,6). Among these various types of brain tumors, studies have been conducted on miRNAs in gliomas, meningiomas and schwannomas (6–10). Notably, certain previous studies have focused on the expression profiles of miRNAs in cancerous tissues and their associations with target genes involved in cancer cell formation and metastasis.
Abnormal expression of miRNAs in glioma tissues was previously reported, and miRNAs, including miR-34a, 146a, 7, 128 and 195, were downregulated in cancer tissues compared with those in normal tissues, suggesting dysregulation of tumor suppressor genes (6). However, the expression of certain miRNAs (miR-21, 26a, 10b, 30e and 221/222) was increased, suggesting that miRNAs act not only as tumor suppressors, but also, dependent on the function of the targeted mRNA, as oncogenes (6,7). The miRNA expression profiling of meningiomas has shown a reduction in miR-29c and miR-219 depending on the tumor grade and has indicated that high expression of miR-190a in meningiomas correlates with tumorigenic risk. In addition, the expression pattern of miR-190a is a prognostic predictor of postoperative outcome (8). In addition, the expression patterns of miRNAs, including miR-200a and miR-145, are reportedly associated with the progression of meningiomas (9). A schwannoma study also showed altered miRNA expression patterns in tumor tissues, with 8 miRNAs showing increased expression and 4 miRNAs showing decreased expression in tumor tissues compared with that in normal tissues (10).
Numerous studies have found a correlation between miR-146a, 149, 196a2 and 499 and tumorigenesis and tumor suppression. These miRNAs are associated with tumor initiation, invasion, metastasis and proliferation through a variety of mechanisms, and can also function as tumor suppressor genes (4,11–13). Thus, previous studies of miRNA have focused on miRNA regulation and its influence on tumorigenesis. Nevertheless, the reasons for the widespread differential expression of miRNAs in malignant cells compared with that in normal cells are not fully elucidated.
Previous studies have reported miRNA polymorphisms in various cancer types. miRNA single nucleotide polymorphisms (SNPs) have been found to be associated with carcinogenesis, progression, development and prognosis (14,15). SNPs are known to affect miRNA expression and maturation (16). miR-146aC>G, miR-149C>T, miR-196a2C>T and miR-499A>G are well-known miRNA SNPs, and among these, three variants (miR-146aC>G, miR-196a2C>T and miR-499A>G) are located in the mature form of the sequence, and the remaining variant (miR-149C>T) is located in the precursor form of the sequence. A previous study (14) reported that increased expression of the miR-196a2C>T polymorphism was associated with a decreased survival rate in patients with lung cancer. In addition, other studies have reported significant associations between the miR-196a2C>T polymorphism and the prevalence of various cancer types and heart disease (17–22). Furthermore, previous studies have suggested that miR-146aC>G, miR-149C>T and miR-499A>G variants are associated with heart disease and esophageal cancer (18,19,22).
Recently, reports have found an association between miRNAs and brain tumors. However, the function of miRNA polymorphisms in brain tumors is unclear in terms of the pathogenesis, and the majority of studies have been limited to specific tumors. The results of these studies have been inconsistent (11,14–24). Thus, the present study sought to investigate the frequency of four miRNA polymorphisms (146aC>G, 149C>T, 196aC>T and 499A>G) in brain tumors, specifically gliomas, meningiomas and schwannomas.
Materials and methods
Study population
A total of 362 patients were enrolled, including 179 with brain tumors and 183 healthy controls. Patients with brain tumors were diagnosed through imaging examinations, including computed tomography and magnetic resonance imaging, and were confirmed to have gliomas, meningiomas or schwannomas through histopathological studies following surgical resection. Adults who underwent a general health care examination at CHA Bundang Hospital (Seongnam, South Korea) and who had no history of tumors, brain diseases, including Alzheimer's disease, dementia, stroke or intracerebral hemorrhage, or other underlying diseases were selected for the control group. All study participants were fully informed and received an explanation of the study, and provided written informed consent; individuals who did not agree to the study were excluded.
Genetic analysis
Genomic DNA was extracted using the G-DEX blood kit (iNtRON Biotechnology, Inc., Seongnam, South Korea) from anticoagulated peripheral blood, as previously described (25). The four miRNA polymorphisms of interest (miR-146a, 149, 196a2 and 499) were identified by a literature search using the key words ‘miRNA’ and ‘brain tumor’ in Pubmed (https://www.ncbi.nlm.nih.gov/pubmed). The genotype examination conditions outlined in our previous study protocol were used (25). Samples underwent re-genotyping examination by an additional operator for confirmation. In addition, 20% of the total samples were randomly selected and the four miRNA polymorphisms were confirmed by sequencing (ABI3730Xl DNA analyzer; Applied Biosystem; Thermo Fisher Scientific, Inc., Waltham, MA, USA). PCR was performed with conditions and primer and probe sequences as detailed in our previous study (25).
Statistical analysis
The genotype and allele frequencies for miRNA polymorphisms in the patients with brain tumors and the controls were determined. The differences in the genotypes and allele frequencies were analyzed using the χ2 test and Fisher's exact test, respectively. Allelic frequencies included calculated deviations based on the Hardy-Weinberg equilibrium, using P<0.05 as a threshold (26). As the inferences of the present study were derived from multiple tests, the Benjamini and Hochberg strategy was adopted, which effectively reduced the potential impact of spurious significant results (27). Statistical analyses were performed that measured the efficacy of the association between brain tumor and genotype based on multivariable logistic regression and according to the statistical methods discussed by Kim and Hong (28). The multifactor dimensionality reduction method has been described in detail previously (29–33). In addition, all possible allele-allelic combinations were performed using HAPSTAT software (v.3.0; www.bios.unc.edu/~lin/hapstat/). Survival analysis estimated the adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs), with adjustment for age by multivariate Cox proportion hazards regression.
Results
Participant characteristics
A total of 362 participants whose aged from 21 to 85 years were enrolled in the present study, including 183 healthy controls (age range, 24–85 years) and 179 patients (age range, 21–78 years) with brain tumors. In the brain tumor group, 79 patients had gliomas, 69 had meningiomas and 31 had schwannomas. The male:female ratio for all participants was 1:1.48 (1:1.88 for the control group and 1:1.16 for the brain tumor group). The mean age of all participants was 48.8±15.9 years (control group mean, 45.9±16.6 years; brain tumor group mean, 51.9±14.7 years) (Table I).
Genetic analysis
The miR-146a rs2910164, miR-149 rs4846049, miR-196a2 rs11614913 and miR-499 rs3746444 polymorphisms were compared between the brain tumor and control groups. Participant genotype and allelic frequencies of the four miRNA polymorphisms are detailed in Table II. Analysis by tumor type found that the frequencies of the dominant miR-149 genotype [odds ratio (OR), 1.842; 95% CI, 1.074–3.159; P=0.02] and CC type of miR-149 (OR, 2.771; 95% CI, 1.158–6.635; P=0.02) were significantly increased compared with those of the TT and TC genotypes for gliomas. The frequencies of the miR-146a, miR-149, miR-196a2 and miR-499 genotypes were not significantly different between the control group and the meningioma or schwannoma patient groups.
 | Table II.Genotype frequencies of miRNA polymorphisms between patients with three different brain tumor subtypes [glioma (n=79), meningioma (n=69) and schwannoma (n=31)] and control subjects (n=183). |
Allele combination analysis according to subgroup
ORs for gliomas, meningiomas and schwannomas are detailed in Tables III, IV and V, respectively. The ORs for glioma were increased in the following combinations: i) CCCG, CTCG and GCTG haplotypes of miR-146aC>G, miR-149T>C, miR-196a2T>C and miR-499A>G; ii) GCT haplotype of miR-146aC>G, miR-149T>C and miR-196a2T>C; iii) CCG haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G; iv) GC haplotype of miR-146aC>G and miR-149T>C; and v) CA haplotype of miR-149T>C and miR-499A>G (Table III). For meningiomas, the ORs were increased in the following combinations: i) GTCG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C and miR-499A>G; ii) GCG haplotype of miR-146aC>G, miR-196a2T>C and miR-499A>G; and iii) CCG haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G (Table IV). The ORs for schwannomas were increased in the following combinations: i) GCTG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C and miR-499A>G; and ii) CCG haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G (Table V).
| Table III.Allele combination of miRNA polymorphisms between glioma patients (2n=158) and control subjects (2n=366). |
| Table IV.Allele combination of miRNA polymorphisms between patients with meningioma (2n=138) and control subjects (2n=366). |
| Table V.Allele combination of miRNA polymorphisms between patients with Schwannoma (2n=62) and control subjects (2n=366). |
Multivariate survival analysis according to genotypes
Fig. 1 shows the association between the overall survival (OS) of patients with brain tumors and the four pre-miRNA SNPs. No significant association was found between OS and miR-146a, miR-149 or miR-499; however, miR-196a2T>C was associated with a significantly shorter OS time (adjusted HR, 2.094; 95% CI, 1.147–3.823; P=0.017; Fig. 1). Additionally, when OS was analyzed according to the dominant genotype (TT vs. TC+CC), a poorer OS time was associated with the miR-196a2 C allele (HR, 1.809; 95% CI, 1.043–3.137; P=0.036; Fig. 1).
Discussion
Brain tumors can cause severe impairment and impose a decreased quality of life, often resulting in mortality (34,35). The overall incidence rate of all brain tumors is 10.82 per 100,000 person-years (36). In the 2013 Central Brain Tumor Registry of the United States report, the average annual age-adjusted incidence rate of glioblastoma was 3.19 per 100,000 individuals, which was the highest incidence among all types of brain and central nervous system (CNS) tumors. Meningioma is the second most common type of brain tumor (37). Sex and age standardized incidence rates range from 1.28 per 100,000 individuals to 7.80 per 100,000 individuals for cerebral meningioma. The overall incidence rate of schwannomas was 1.2 per 100,000 individuals per year in the United States in the period between 2004 and 2009 (38).
Studies on the pathogenesis of brain tumors are ongoing. For several decades, studies have identified molecular alterations characterizing gliomas and reported decreased expression of tumor suppressor genes, such as retinoblastoma transcriptional corepressor 1 and p53, or alterations of genes in pathways associated with tumor suppressors (39). In addition, genetic variants, including isocitrate dehydrogenase 1 and phosphatase and tensin homolog (PTEN), have been reported in gliomas (40–42). Chromosomal anomalies, aberrant cellular pathways and alterations in tumor suppressor genes are associated with meningioma pathogenesis (43–46). Schwannomas are directly associated with genetic changes in neurofibromin 2 gene inactivation (47). However, no clear mechanism of the pathogenesis for all brain tumors has been identified.
miRNAs regulate target gene expression at the post-transcriptional level. miRNAs control key physiological processes, including cell growth, differentiation and apoptosis, which suggests that miRNA gene abnormality could be involved in tumorigenesis (1–3,48). The correlation between cancer and miRNAs was established in 2002 (49). Certain miRNA abnormalities have been associated with cancer types, and with carcinogenesis and progression (1,3–5). The results reported in the present study suggest that identifying miRNAs and their targets may provide potential diagnostic and prognostic tumor biomarkers and novel cancer therapeutic strategies. Studies of miRNAs associated with brain tumors are ongoing. miRNAs are associated with regulation of tumorigenic cells in CNS tumors, and certain miRNAs are oncogenes (4,50,51). miRNAs also regulate tumor invasion, metastasis and cell apoptosis, and are involved in tumor chemoresistance and radioresistance (52–54).
Recent epidemiological studies have demonstrated that miRNA variants cause altered expression and are associated with the risk of cancer (55). For example, miRNA-146a antagonizes the expression of interleukin (IL)-1β, tumor necrosis factor-α and nuclear factor-κB (56). miR-146a is known to be important for tumor proliferation and metastatic ability (23). In addition, certain studies have suggested that miR-196a dysfunction is associated with tumor abnormality (13). miR-196a2 has a double mature strand containing a 5′-end strand (hsa-miR-196a2−5p) and a 3′-end strand (hsa-miR-196a2−3p), and the miR-196a2 rs11614913 T>C polymorphism is located in the hsa-miR-196a-3p sequence. The rs11612913 SNP may influence the maturation of hsa-miR-196a. In other words, this polymorphism may affect or alter the expression of the target, which may be involved in regulating carcinogenesis. Several studies have identified miR-499A>G as a potential marker for a number of cancer types, including breast cancer, gastric cancer, squamous cell carcinoma and hepatocellular carcinoma (11,14,24). The miR-499 rs3746444 A>G polymorphism is located in the stem loop. To date, few studies have investigated rs2292932 in miR-149 compared with the three other genes. Li et al (12) suggested that miR-149 inhibits associated fibroblasts by regulating prostaglandin E2 and IL-6 in tumor cells (12).
The present study identified the genotypic distribution of the four most common miRNAs associated with tumors (i.e., miR-146a, miR-149, miR-196a2 and miR-499) in patients with glioma, meningioma or schwannoma. In this Korean population, the frequencies of the dominant miR-149 genotype and the CC genotype were significantly increased compared with those of the TT and TC genotypes in the patients with glioma. However, the frequency of the miR-146a rs2910164 C>G, 196a2 rs11614913 T>C and 499 rs3746444 A>G polymorphisms were not significantly different between the control group and the tumor group. To date, there have been considerably fewer studies on miR-149 than on other miRNAs, particularly concerning the association of miR-149 with brain tumors. One previous study of the association between miR-149 and brain tumors reported that increased miR-149 levels downregulate tumor proliferation and metastasis in glioblastoma (57). miR-149 regulates cell cycle-related genes and controls potential proliferation and invasion activity of glioma cells through a mechanism that induces arrest at the G0/G1 phase (58). However, the manner in which miRNAs affect tumorigenesis or suppression of brain tumors is not yet known, and the results differ by study and participant ethnicity. Analysis of haplotype frequencies according to brain tumor type showed that odds ratios were higher in certain haplotypes in the present study. In particular, the GCTG haplotype of miR-146aC>G, miR-149T>C, miR-196a2T>C and miR-499A>G had increased the ORs for gliomas and schwannomas. The CCG haplotype of miR-149T>C, miR-196a2T>C and miR-499A>G showed increased ORs for all three types of brain tumors. However, the mechanism by which certain haplotypes simultaneously increase the risk for various tumors has not been determined.
The miR-196a2 rs11614913C allele has been reported to be associated with the risk of various cancer types in several studies. Hu et al (14) showed that the miR-196a2 rs11614913C allele was associated with a significant risk of breast cancer. In addition, Tian et al (17) demonstrated that the miR-196a2 rs11614913 CC type posed a significant risk of lung cancer in Chinese individuals. Moreover, several studies suggested the association of the miR-196a2C allele with an elevated risk of various cancer types, including hepatoma, gastric cancer and esophageal squamous cell carcinoma (20–22). To date, there have been only two reports on the effects of an association between miR-196a2 and brain tumor prognosis (59,60). The present study showed that the miR-196a2T>C polymorphism was a significant factor for mortality in Korean patients with brain tumors. However, as the survival analysis included the entire brain tumor group, care must be taken when interpreting these results.
The present study had several limitations. First, the way in which miRNA genetic variants affect brain tumor progression remains unclear. Second, in this study, the expression patterns of the four miRNAs in gliomas, meningiomas and schwannomas samples could not be identified as the biopsy samples were in poor condition and the number of tissue samples was insufficient. Therefore, the acquisition of tissue samples is currently being attempted and further studies are being planned. Third, the sample size of this study is limited in number. Lastly, the analysis was performed in a solely Korean population. Although the results present the first evidence for utilization of miRNA polymorphisms as diagnostic and prognostic markers of brain tumor risk, further research in large and diverse cohorts is necessary. Based on the results from this study, a future large-population study is required to identify the association between brain tumors and miRNAs beyond the four miRNAs tested here. In addition, the expression patterns of miRNAs in brain tumors and normal tissues require further study, as does the function of cultured cell lines derived from brain tumors, including gliomas, meningiomas and schwannomas. Additional studies will also be necessary to determine the mechanism by which miRNAs affect carcinogenesis and tumor progression. In conclusion, the present study analyzed the association between the miR-149 rs2292832 C>T polymorphism and glioma susceptibility and found allele-allelic combinations in which miRNA polymorphisms were positively associated with glioma, meningioma and schwannoma susceptibility.
Acknowledgements
The abstract of this paper was presented at the 5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies, May 4–7, 2017, in Zurich, Switzerland, and was published as Abstract no. p08.33 in Neuro-Oncology (Suppl 3) 2017.
Funding
This study was supported by the Industrial Technology Innovation Program through the Ministry of Trade, Industry and Energy (Korea), funded by the Ministry of Trade, Industry and Energy, Republic of Korea (grant no. 10067378), and supported by a grant of the Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant no. HI15C1972010015).
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
KC and NKK conceived and designed the experiments. JOK and HSP performed the experiments. JL, JOK, HSP, IBH, KK, KC and NKK analyzed the data. JL, JOK, HSP, IBH, KC and NKK were responsible for reagents, materials and analysis tools. JL and JOK wrote the paper. KC and NKK performed the article editing.
Ethics approval and consent to participate
All study protocols were reviewed and approved by The Institutional Review Board of CHA Bundang Medical Center (Seongnam, South Korea) and followed the recommendations of the Declaration of Helsinki. All patients provided written informed consent.
Patient consent for publication
All patients provided written informed consent for publication.
Competing interests
The authors have no competing interests to declare.
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