Abstract
Much evidence indicates that microRNAs could play potential roles as diagnostic and prognostic biomarkers of human cancers, including hepatocellular carcinoma (HCC). The present meta-analysis aimed to systematically evaluate the diagnostic accuracy of circulating microRNAs for HCC. Eligible studies were identified through multiple search strategies and assessed for relevance and quality. Results from different studies were pooled using random-effects models. The quality of each study was scored with the revised quality assessment of diagnostic accuracy studies tool. The summary receiver operator characteristic (SROC) curve and other measures were used to assess the overall performance of microRNA-based assays. Evidence of heterogeneity was evaluated using the I 2 test. Meta-regressions were conducted to analyze potential sources of heterogeneity. Deeks’ test was used to test for potential publication bias. Thirty studies from 13 publications, including 1,314 patients with HCC and 1,407 controls, comprised healthy individuals and patients with hepatitis B/C or cirrhosis, were included in this meta-analysis. For diagnostic meta-analysis, the overall pooled results were as follows: sensitivity was 0.80 (95 % CI 0.74–0.84), specificity was 0.81 (95 % CI 0.74–0.87), positive likelihood ratio was 4.2 (95 % CI 3.0–6.0), negative likelihood ratio was 0.25 (95 % CI 0.19–0.38) and diagnostic odds ratio was 17 (95 % CI 10–29). The area under the SROC curve was 0.86 (95 % CI 0.84–0.90). Subgroup analyses suggested that multiple microRNAs had much better accuracy than single microRNA. Our findings suggest that circulating microRNAs show significant potential as diagnostic markers of HCC, particularly when using multiple microRNAs. However the results of this meta-analysis justify larger, more rigorous studies to confirm our conclusions.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108
Yuen MF, Hou JL, Chutaputti A (2009) Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol 24(3):346–353
Kew MC (2010) Epidemiology of chronic hepatitis B virus infection, hepatocellular carcinoma, and hepatitis B virus-induced hepatocellular carcinoma. Pathol Biol (Paris) 58(4):273–277
El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576
Zinkin NT, Grall F, Bhaskar K, Otu HH, Spentzos D, Kalmowitz B, Wells M, Guerrero M, Asara JM, Libermann TA, Afdhal NH (2008) Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res 14(2):470–477
Schwartz M, Roayaie S, Konstadoulakis M (2007) Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol 4(7):424–432
Fukuda S, Itamoto T, Nakahara H, Kohashi T, Ohdan H, Hino H, Ochi M, Tashiro H, Asahara T (2005) Clinicopathologic features and prognostic factors of resected solitary small-sized hepatocellular carcinoma. Hepatogastroenterology 52(64):1163–1167
Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai CL (2000) Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 31(2):330–335
Benson AB, Abrams TA, Ben-Josef E, Bloomston PM, Botha JF, Clary BM, Covey A, Curley SA, D’Angelica MI, Davila R, Ensminger WD, Gibbs JF, Laheru D, Malafa MP, Marrero J, Meranze SG, Mulvihill SJ, Park JO, Posey JA, Sachdev J, Salem R, Sigurdson ER, Sofocleous C, Vauthey JN, Venook AP, Goff LW, Yen Y, Zhu AX (2009) NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Cancer Netw 7(4):350–391
Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST, Poon RT, Gao C, Luk JM (2012) Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2(2):e000825
Johnson PJ (2001) The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 5(1):145–159
el-Houseini ME, Mohammed MS, Elshemey WM, Hussein TD, Desouky OS, Elsayed AA (2005) Enhanced detection of hepatocellular carcinoma. Cancer Control 12(4):248–253
Ambros V (2004) The functions of animal microRNAs. Nature 431(7006):350–355
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM (2006) MicroRNA expression and function in cancer. Trends Mol Med 12(12):580–587
Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6(11):857–866
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Zen K, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105(30):10513–10518
Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K (2010) Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res 70(23):9798–9807
Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF (2011) Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One 6(12):e28486
Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, Huang L, Li H, Tan W, Wang C, Lin D (2011) Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 50(2):136–142
Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z, Wang JF, Zhang Z, Lu S, Huang X, Wang Z, Qiu S, Wang X, Yang G, Sun H, Tang Z, Wu Y, Zhu H, Fan J (2011) Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 29(36):4781–4788
Li L, Guo Z, Wang J, Mao Y, Gao Q (2012) Serum miR-18a: a potential marker for hepatitis B virus-related hepatocellular carcinoma screening. Dig Dis Sci 57(11):2910–2916
Luo J, Chen M, Huang H, Yuan T, Zhang M, Zhang K, Deng S (2013) Circulating microRNA-122a as a diagnostic marker for hepatocellular carcinoma. Onco Targets Ther 6:577–583
Wei R, Huang GL, Zhang MY, Li BK, Zhang HZ, Shi M, Chen XQ, Huang L, Zhou QM, Jia WH, Zheng XF, Yuan YF, Wang HY (2013) Clinical significance and prognostic value of microRNA expression signatures in hepatocellular carcinoma. Clin Cancer Res 19(17):4780–4791
Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M (2011) Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol 45(4):355–360
Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM (2008) Systematic reviews of diagnostic test accuracy. Ann Intern Med 149(12):889–897
Barker FG 2nd, Carter BS (2005) Synthesizing medical evidence: systematic reviews and metaanalyses. Neurosurg Focus 19(4):E5
Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM (2011) QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 155(8):529–536
Deville WL, Buntinx F, Bouter LM, Montori VM, de Vet HC, van der Windt DA, Bezemer PD (2002) Conducting systematic reviews of diagnostic studies: didactic guidelines. BMC Med Res Methodol 2:9
Mitchell AJ, Vaze A, Rao S (2009) Clinical diagnosis of depression in primary care: a meta-analysis. Lancet 374(9690):609–619
Walter SD (2002) Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med 21(9):1237–1256
Jones CM, Athanasiou T (2005) Summary receiver operating characteristic curve analysis techniques in the evaluation of diagnostic tests. Ann Thorac Surg 79(1):16–20
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Dinnes J, Deeks J, Kirby J, Roderick P (2005) A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy. Health Technol Assess 9(12):1–113 iii
Deeks JJ, Macaskill P, Irwig L (2005) The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol 58(9):882–893
Abdalla MA, Haj-Ahmad Y (2012) Promising candidate urinary microRNA biomarkers for the early detection of hepatocellular carcinoma among high-risk hepatitis C virus Egyptian patients. J Cancer 3:19–31
Tomimaru Y, Eguchi H, Nagano H, Wada H, Kobayashi S, Marubashi S, Tanemura M, Tomokuni A, Takemasa I, Umeshita K, Kanto T, Doki Y, Mori M (2012) Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol 56(1):167–175
Liang Z, Gao Y, Shi W, Zhai D, Li S, Jing L, Guo H, Liu T, Wang Y, Du Z (2013) Expression and significance of microRNA-183 in hepatocellular carcinoma. ScientificWorldJournal 2013:381874
Shen J, Wang A, Wang Q, Gurvich I, Siegel AB, Remotti H, Santella RM (2013) Exploration of genome-wide circulating microRNA in hepatocellular carcinoma: miR-483-5p as a potential biomarker. Cancer Epidemiol Biomarkers Prev 22(12):2364–2373
Li T, Yin J, Yuan L, Wang S, Yang L, Du X, Lu J (2014) Downregulation of microRNA-139 is associated with hepatocellular carcinoma risk and short-term survival. Oncol Rep 31:1699–1706
Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M (2008) MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 47(4):1223–1232
He QY, Zhu R, Lei T, Ng MY, Luk JM, Sham P, Lau GK, Chiu JF (2008) Toward the proteomic identification of biomarkers for the prediction of HBV related hepatocellular carcinoma. J Cell Biochem 103(3):740–752
Collier J, Sherman M (1998) Screening for hepatocellular carcinoma. Hepatology 27(1):273–278
Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM (2003) The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol 56(11):1129–1135
Deeks JJ, Altman DG (2004) Diagnostic tests 4: likelihood ratios. BMJ 329(7458):168–169
Wang D, Mou ZY, Zhai JX, Zong HX, Zhao XD (2008) Application of Stata software to test heterogeneity in meta-analysis method. Zhonghua Liu Xing Bing Xue Za Zhi 29(7):726–729
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This work was supported by a grant from the National Natural Sciences Foundation of China (No. 81102692).
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Yang, Y., Zhu, R. Diagnostic value of circulating microRNAs for hepatocellular carcinoma. Mol Biol Rep 41, 6919–6929 (2014). https://doi.org/10.1007/s11033-014-3578-7
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DOI: https://doi.org/10.1007/s11033-014-3578-7