|Year : 2014 | Volume
| Issue : 7 | Page : 173-178
Diagnostic value of circulating microRNAs for nasopharyngeal cancer: A systematic review and meta-analysis
Zhiyi Wang, Wei Chen, Yong Zhang, Li Xu, Qiuping Wang
Department of Otolaryngology Head and Neck Surgery, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu 210002, China
|Date of Web Publication||29-Nov-2014|
Department of Otolaryngology Head and Neck Surgery, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu 210002
Source of Support: None, Conflict of Interest: None
Aim: Circulating microRNAs (miRNA) are a promising diagnostic tool for lung and gastric cancer. However, their diagnostic value in nasopharyngeal cancer remains unknown. Thus, this study aims to systematically evaluate the diagnostic accuracy of circulating miRNA for nasopharyngeal cancer.
Method: Eligible studies were searched and selected from the PubMed, EMBASE, and Cochrane CENTRAL databases. Results from these included studies were pooled using random-effects models. Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were calculated to assess the overall performance of miRNA-based assay. Summary receiver operating characteristic (SROC) curves were plotted to evaluate the overall diagnostic accuracy of circulating miRNA detection.
Results: Seven publications were considered eligible for this systematic review, and four studies were finally chosen for this meta-analysis. In the diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, PLR, NLR, and DOR were 0.87 (95% confidence interval [CI]: 0.83-0.90), 0.87 (95% CI: 0.82-0.91), 7.529 (95% CI, 2.575-22.013), 0.145 (95% CI, 0.058-0.363), and 64.045 (95% CI, 10.176-403.10), respectively. The area under SROC curve was 0.95.
Conclusion: Circulating miRNA detection presents an enormous potential in diagnosing nasopharyngeal cancer. Studies with a large sample size of nasopharyngeal cancer patients must be conducted to verify the diagnostic value of circulating miRNA.
Keywords: Circulating microRNA, meta-analysis, nasopharyngeal cancer, random-effect model
|How to cite this article:|
Wang Z, Chen W, Zhang Y, Xu L, Wang Q. Diagnostic value of circulating microRNAs for nasopharyngeal cancer: A systematic review and meta-analysis. J Can Res Ther 2014;10, Suppl S3:173-8
|How to cite this URL:|
Wang Z, Chen W, Zhang Y, Xu L, Wang Q. Diagnostic value of circulating microRNAs for nasopharyngeal cancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2014 [cited 2019 Oct 17];10:173-8. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/173/145858
| > Introduction|| |
Nasopharyngeal carcinoma (NPC) is a type of head and neck tumor with a complicated etiology and a distinct geographic distribution, with high incidence rates in Southern China and Southeastern Asia. The incidence of NPC in Southern China is approximately 15-25 cases/100,000 people while less than 1 case/100,000 individuals in Western countries.  Being asymptomatic, NPC tumors usually have developed into the advanced phase when diagnosed.  Although radiotherapy and chemotherapy are efficient approaches to NPC tumors, the disease is still capable of local or loco-regional recurrence, lymph node metastasis, and distant metastasis, which greatly contribute to the high mortality of this disease.  Therefore, NPC development must be clearly understood to provide potential diagnostic and prognostic biomarkers and therapeutic targets.
MicroRNA (miRNA), a 19-25 nucleotide small RNA, participates in various biological activities, including apoptosis, cellular differentiation, embryogenesis, angiogenesis, metabolism, and immune responses.  Abnormal miRNA expression is closely correlated with various diseases, particularly cancer. , Many miRNAs are aberrantly expressed in NPC and involved in various signaling pathways, indicating that miRNAs greatly influence the initiation and progression of NPC. ,,, Epstein-Barr virus (EBV) is the first human virus found to encode miRNAs within the BHRF1 and BART regions of its genome, indicating that EBV-encoded miRNAs are involved in the pathological process of NPC.  To date, at least 25 EBV miRNA hairpins and 44 mature miRNAs have been identified, among which miR-BARTs are prevalently abundant and most studied in NPC. , Several comprehensive profiling studies have found through microarray methods and bioinformatics tools that differentially expressed EBV-encoded miRNAs are potential biomarkers for NPC. , However, the clinical significance of miRNAs in NPC has yet to be elucidated.
Circulating miRNAs, which are detected in cell-free body fluids such as serum and plasma, are protected by ribonucleases in the blood from degradation and thus are stable.  Mitchell et al., were the first to report the potential of circulating miRNAs as biomarkers for cancer detection. Since then, many studies have been carried out to detect miRNA expression in the peripheral blood of patients with various tumors, including NPC. miRNA-based blood test is less invasive, relatively inexpensive, and easily reproducible; thus, using circulating miRNAs as biomarkers would dramatically improve the detection and treatment of NPC. Several studies have demonstrated the diagnostic utility of circulating miRNAs, including EBV-encoded miRNAs, in NPC. However, the results of these studies are inconsistent, which limits the selection of suitable miRNAs as diagnostic biomarkers and delays their further application in clinical treatment.
In this study, we collected eligible studies that compared miRNA expression in blood samples of NPC patients with corresponding controls and then performed a meta-analysis of the included studies to evaluate the diagnostic accuracy of using circulating miRNAs as biomarkers for NPC.
| > Methods|| |
0 Literature search and study selection
The following search terms were used to conduct a literature search in the PubMed, EMBASE, and Cochrane databases: "Nasopharyngeal cancer," "miRNA," "circulating blood," and "serum." We also manually searched the reference lists of the included studies. Only manuscripts published in English and focusing on human samples were considered in this meta-analysis.
Studies were included in this meta-analysis on the basis of the following criteria: (1) Diagnostic studies focused on circulating miRNAs for NPC; (2) diagnosis for NPC was confirmed by histopathological or cytological examinations following the reference standard; (3) sample types were whole blood, serum, or plasma; and (4) sufficient data were provided to generate a 2 × 2 table for calculating sensitivity and specificity. Hence, studies that used biopsy-based tissue and cell lines were excluded. Studies that used fewer than 20 patients or did not include a control group were also excluded to avoid selection bias. Conference abstracts were excluded because of insufficient data. Two authors independently reviewed the manuscripts for eligible articles. Disagreements were solved through discussion with a third person to reach a consensus.
Data extraction and quality assessment
Two authors independently reviewed the final enrolled articles and retrieved the following data from each report: (1) Trial features such as first author, publication year, and country; (2) participants' general information, including number of patients and corresponding control subjects, gender, age, and pathological staging; (3) miRNA detection method; (4) miRNA expression profiles; and (5) data necessary for diagnostic meta-analysis, such as sensitivity and specificity. When studies contained both training and validating cohorts, each cohort was treated as an independent study in the meta-analysis.
The Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) tool, which is a widely accepted assessment in systematic reviews of diagnostic accuracy studies, was used to evaluate the methodological quality of each included study. ,
Standard methods recommended for the meta-analyses of diagnostic accuracy studies were used.  All analyses were performed using Meta-DiSc 1.4 (Cochrane Colloquium, Barcelona, Spain) and RevMan (version 5.3). Review Manager (RevMan) is the software used for preparing and maintaining Cochrane Reviews.Moreover,it can perform meta-analyses and present the results graphically. All statistical tests were two-sided, and significance was set as P < 0.05.
Five indices of diagnostic accuracy, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR), were calculated for each study together with 95% confidence intervals (CIs). A summary receiver operating characteristic (SROC) curve was plotted on the basis of the sensitivity and specificity of each study.  Threshold effects were detected by Spearman rank correlation, which was calculated between the sensitivity logarithm and (1-specificity) logarithm. P < 0.05 was considered to indicate positive correlation between sensitivity logarithm and (1-specificity) logarithm as well as the presence of threshold effects. Otherwise, the I2 value was used to evaluate heterogeneity between studies. Substantial heterogeneity was considered at I2 ≥ 50%. Furthermore, a meta-regression was performed according to the features of the included studies to identify the source of heterogeneity.
| > Results|| |
0 Literature search
After systematic database searches and manual review of reference lists in eligible studies, a total of 23 publications were preliminarily included. Basing on the inclusion and exclusion criteria, we included seven publications that contain nine studies on the diagnostic accuracy of circulating miRNA in NPC patients. ,,,,,,, The flow of search strategy is shown in [Figure 1].
Comparison of expression levels of circulating microRNAs between nasopharyngeal carcinoma patients and healthy individuals
[Table 1] lists the characteristics of the seven publications that compared circulating miRNA expression between NPC patients and healthy individuals. These characteristics include miRNA detection methods, samples, and sample size. Six of the seven studies were performed in China, and one was performed in France. Quantitative polymerase chain reaction was used in all studies to detect circulating miRNA expression in the serum or plasma samples. Almost all studies applied TaqMan miRNA assay, except for one group that used SYBR Green assay kit (QIAGEN, Valencia, CA). A total of 17 miRNA, including two EBV-encoded miRNAs and 15 cellular miRNAs, were detected in these studies [Table 2]. Only miR-483-5p was reported in two studies.
|Table 1: The characteristics of eligible studies included in this systematic review |
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|Table 2: Eighteen miRNAs expression level (NPC patients vs. noncancerous controls) |
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In these publications, only four articles containing five studies that provided sufficient diagnostic test data, such as sensitivity and specificity, were included in the meta-analysis and underwent methodological quality assessment based on QUADAS-2. These articles involved 539 participants comprising 388 NPC patients and 151 healthy controls. In brief, the overall quality of study design and reporting diagnostic accuracy were assessed as good because almost all studies fulfilled most parts of the items listed in QUADAS. However, we assessed the studies as "unclear" for the index test because none stated whether or not the interpretation of circulating miRNA results was independent of the reference standard. The overall quality assessment, including risk of bias and applicability concerns, is presented as a bar graph in [Figure 2]. [Table 3] lists the detection methods, sample size, and detection results, including true positive, false positive, false negative (FN), and true negative, for each study. Although the three other articles also reported area under receiver operating characteristic curve (AUC) values, they were not included in the meta-analysis because of insufficient evidence. The clinical value of these articles will be discussed later.
|Figure 2: Overall quality assessment of included studies by using Quality Assessment for Studies of Diagnostic Accuracy-2 tool. Left panel: Proportion of studies with low (green), high (red) or unclear (yellow) risk of bias. Right panel: Proportion of studies with low, high, or unclear concerns regarding applicability|
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[Figure 3] and [Figure 4] display the forest plot of the sensitivity and specificity of circulating miRNA detection for diagnosing NPC patients in five studies. The pooled sensitivity and specificity for the diagnosis of NPC were 0.87 (95% CI: 0.83-0.90, P = 0.0000) and 0.87 (95% CI: 0.82-0.91, P = 0.0001), respectively. In addition, the pooled PLR and NLR were 7.529 (95% CI: 2.575-22.013, P = 0.0001) and 0.145 (95% CI: 0.058-0.363, P = 0.0000), respectively. The DOR was 64.045 (95% CI: 10.176-403.10, P = 0.0000). These data [Table 4] indicate that circulating miRNA detection can differentiate NPC from healthy controls. The I2 values for sensitivity and specificity were 86.3% and 83.1%, respectively, implying significant heterogeneity between studies. The spearman correlation coefficient was calculated to be − 0.8 (P = 0.104), indicating no threshold effects. The SROC curve for the included studies is presented in [Figure 5]. The AUC and Q-value were 0.95 and 0.89, respectively, suggesting a high overall diagnostic accuracy.
|Figure 3: Forest plot of sensitivity of circulating microRNAs for the diagnosis of nasopharyngeal carcinoma. The point representing the sensitivity of each study are shown as solid circles. Error bars indicate 95% confidential intervals|
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|Figure 4: Forest plot of specificity of circulating microRNAs for the diagnosis of nasopharyngeal carcinoma. The points representing the specificity of each study are shown as solid circles. Error bars indicate 95% confidential intervals|
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|Figure 5: Summary receiver operating characteristic (SROC) curve of circulating microRNAs for the diagnosis of nasopharyngeal carcinoma. The size of each solid circle represents the size of each study in the meta-analysis. The regression SROC curve indicates the overall diagnostic accuracy|
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|Table 4: Summary of five diagnostic indices for circulating miRNAs detection |
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| > Discussion|| |
The development of suitable biomarkers is critical for cancer diagnosis, especially for cancers with less obvious symptoms, such as NPC. Recently, circulating miRNA have attracted considerable attention due to their high stability and convenience. Circulating miRNA have also exhibited great potential as biomarkers. Several studies have been carried out to detect circulating miRNA in various tumors, including NPC. Other studies evaluated the diagnostic potential of circulating miRNA for lung cancer, , gastric cancer,  and pancreatic cancer. , However, to the best of our knowledge, the current study is the first systematic review and meta-analysis that evaluates the diagnostic value of circulating miRNA for NPC.
In this meta-analysis, circulating miRNA detection in the peripheral blood of NPC patients exhibited a significant potential diagnostic value, as evidenced by its high sensitivity (0.87, 95% CI: 0.83-0.90) and medium specificity (0.87, 95% CI: 0.82-0.91). Considering that likelihood ratios are clinically useful,  we calculated the PLR and NLR of circulating miRNA detection in NPC patients. The pooled PLR was 7.529, indicating that NPC patients had more than 7-fold higher chance of carrying positive circulating miRNA test results than healthy people. However, the PLR was below 10. Thus, circulating miRNA detection is not sufficiently strong to confirm the occurrence of NPC. Meanwhile, the pooled NLR was 0.145, suggesting that <15% chance of negative circulating miRNA test results is likely to be a FN, which is not low enough to rule out NPC. DOR is commonly used to evaluate test performance because it represents a single indicator of diagnostic test accuracy that combines sensitivity and specificity data.  Therefore, higher DOR indicates better discriminatory test performance. In this meta-analysis, the DOR value was 64.045. Our AUC was also higher than 0.95, suggesting the overall high diagnostic accuracy of circulating miRNA detection in peripheral blood.
As mentioned earlier, we excluded three articles because of insufficient data to generate a 2 × 2 table, although they provided AUC data. These three studies reported medium to high value of AUC for different miRNA profiles. Wang et al. demonstrated that miR-483-5p, miR-103, and miR-29a show promising diagnostic values for the early detection of NPC while let-7c is suitable for differentiating advanced NPC from healthy controls. In addition, Jones and Athanasiou  briefly reported the AUC for EBV-miR-BART7 (AUC = 0.81), which had an expression level independent from the circulating EBV DNA level. This result is consistent with that of Gourzones et al.,  suggesting that circulating EBV-encoded miRNA can be used as serological markers in the absence of circulating EBV-DNA. Only Lu et al. compared specific miRNA levels between loco-regional and metastasis samples, and demonstrated a high sensitivity (73.7%) and specificity (74.2%) along with a high AUC value (0.743). These results may serve as references for future works to investigate the specific functions of circulating miRNA in distinguishing the different stages of NPC.
Among the seven publications included in this systematic review, three investigated the prognostic potential of miRNA for NPC patients. ,, These studies demonstrated the promising role of circulating miRNAs as reliable prognostic markers. For example, Wang et al. proved that low concentrations of circulating miR-483-5p and miR-103 and high concentrations of miR-29a and let-7c indicate high 5-year overall survival rates. Liu et al., retrospectively analyzed miRNA expression profiles in NPC tissue-based specimens involving 312 NPC patients and 18 noncancerous controls, and further investigated the prognostic value of miRNAs in NPC. They identified a five-miRNA signature and demonstrated that a combination of this signature and the tumor node metastasis (TNM) staging system has a higher prognostic value compared with the TNM staging system alone. Similar results were found in another study, in which a four-miRNA signature was reported, adding prognostic value to the TNM staging system and providing further information for personalized therapy in NPC.  In addition, almost all included studies claimed that the combination of different miRNAs has a higher diagnostic accuracy than each miRNA alone. This view is supported by similar results reported elsewhere. For instance, although miR-21 shows the best performance among five differentially expressed circulating miRNAs (miR-16, miR-21, miR-24, miR-155, and miR-378) in NPC patients, the combination of these five miRNAs yields better diagnosis with increasing sensitivity and specificity.  In lung cancer, miR-21 alone in circulation is an unsuitable candidate for lung cancer diagnosis. , These studies suggested that circulating miRNAs are promising biomarker candidates for NPC and that miRNAs perform better when combined together or with other current diagnostic tests.
The current meta-analysis has several limitations. First, only four articles with limited numbers of NPC patients were included, which may influence the outcomes. The small number of articles hinders reaching a definitive conclusion on the diagnostic accuracy of circulating miRNA detection in NPC patients. Thus, further studies including a large sample size are needed to confirm the conclusions in the current study. Second, the authors of the included studies provided obscure interpretations of index results. We scored "unclear" for this item, which would attenuate diagnostic accuracy. Finally, with the limited number of studies included, we omitted the performance of meta-regression based on the QUADAS scores to assess the effect of study quality on the diagnostic accuracy of circulating miRNA detection in NPC patients. This omission could influence the accuracy of circulating miRNA detection for NPC diagnosis.
| > Conclusion|| |
Circulating miRNA detection exhibits great potential as a biomarker for NPC. Further studies are required to confirm this predictive value. In the near future, circulating miRNA-based assay will prove useful as a clinical test for screening and confirming NPC diagnosis and guiding informative management of personalized treatment.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]