Original Article
Diagnostic value of circulating microRNAs for nasopharyngeal cancer: A systematic review and meta‑analysis ABSTRACT 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. KEY WORDS: Circulating microRNA, meta-analysis, nasopharyngeal cancer, random-effect model
*Zhiyi Wang and Wei Chen contribute equally to this work
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. [1] Being asymptomatic, NPC tumors usually have developed into the advanced phase when diagnosed. [2] 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.[3] Therefore, NPC development must be clearly understood to provide potential diagnostic and prognostic biomarkers and therapeutic targets.
Abnormal miRNA expression is closely correlated with various diseases, particularly cancer.[5,6] Many miRNAs are aberrantly expressed in NPC and involved in various signaling pathways, indicating that miRNAs greatly influence the initiation and progression of NPC.[7‑10] 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.[11] 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.[12,13] Several comprehensive profiling studies have found through microarray methods and bioinformatics tools that differentially expressed EBV‑encoded miRNAs are potential biomarkers for NPC.[14,15] However, the clinical significance of miRNAs in NPC has yet to be elucidated.
MicroRNA (miRNA), a 19–25 nucleotide small RNA, participates in various biological activities, including apoptosis, cellular differentiation, embryogenesis, angiogenesis, metabolism, and immune responses.[4]
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.[16] Mitchell et al.[17,18] were the first
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
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 For correspondence: Prof. Qiuping Wang, Department of Otolaryngology Head and Neck Surgery, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu 210002, China. E‑mail: wangzhiyi8@ hotmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.145858 PMID: *** Quick Response Code:
C173
Wang, et al.: Circulating microRNAs for nasopharyngeal cancer with meta-analysis
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 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. Inclusion criteria 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. C174
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.[19,20] Statistical analysis Standard methods recommended for the meta‑analyses of diagnostic accuracy studies were used.[21] 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
Diagnostic value of circulating microRNAs for nasopharyngeal cancer: A systematic review and meta‑analysis ABSTRACT 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. KEY WORDS: Circulating microRNA, meta-analysis, nasopharyngeal cancer, random-effect model
*Zhiyi Wang and Wei Chen contribute equally to this work
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. [1] Being asymptomatic, NPC tumors usually have developed into the advanced phase when diagnosed. [2] 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.[3] Therefore, NPC development must be clearly understood to provide potential diagnostic and prognostic biomarkers and therapeutic targets.
Abnormal miRNA expression is closely correlated with various diseases, particularly cancer.[5,6] Many miRNAs are aberrantly expressed in NPC and involved in various signaling pathways, indicating that miRNAs greatly influence the initiation and progression of NPC.[7‑10] 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.[11] 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.[12,13] Several comprehensive profiling studies have found through microarray methods and bioinformatics tools that differentially expressed EBV‑encoded miRNAs are potential biomarkers for NPC.[14,15] However, the clinical significance of miRNAs in NPC has yet to be elucidated.
MicroRNA (miRNA), a 19–25 nucleotide small RNA, participates in various biological activities, including apoptosis, cellular differentiation, embryogenesis, angiogenesis, metabolism, and immune responses.[4]
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.[16] Mitchell et al.[17,18] were the first
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
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 For correspondence: Prof. Qiuping Wang, Department of Otolaryngology Head and Neck Surgery, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu 210002, China. E‑mail: wangzhiyi8@ hotmail.com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.145858 PMID: *** Quick Response Code:
C173
Wang, et al.: Circulating microRNAs for nasopharyngeal cancer with meta-analysis
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 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. Inclusion criteria 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. C174
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.[19,20] Statistical analysis Standard methods recommended for the meta‑analyses of diagnostic accuracy studies were used.[21] 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
