Tumor Biology

, Volume 35, Issue 10, pp 10395–10407

MicroRNAs as ideal biomarkers for the diagnosis of lung cancer

Research Article

Abstract

Lung cancer (LC) is one of the most prevalent causes of cancer death with a high mortality rate worldwide. While various sets of microRNAs (miRNAs) have been found to be highly sensitive and specific biomarkers for the early diagnosis of LC (the first word of abstract), conflicting results on their diagnostic accuracy are still present in individual studies. Thus, we aimed to conduct a systematic review and meta-analysis of the published literature to comprehensively assess the diagnostic value of miRNAs for predicting LC. The sensitivity and specificity of each included study were used to plot the summary receiver operator characteristic (SROC) curve and to calculate the area under the SROC curve (AUC). All analyses were performed using the Stata 12.0 software. Twenty-six articles were involved in our meta-analysis, 18 of which focused on single miRNA assays and 15 on multiple miRNA assays. For single miRNA profiling, the pooled parameters calculated from all studies are as follows: sensitivity (SEN), 0.72; specificity (SPE), 0.74; positive likelihood ratio (PLR), 2.7; negative likelihood ratio (NLR), 0.39; and diagnostic odds ratio (DOR), 7. For multiple miRNA profiling, the pooled estimates for the overall studies are as follows: SEN, 0.81; SPE, 0.84; PLR, 4.9; NLR, 0.23; and DOR, 22, which are significantly better than the diagnostic performance of the single miRNA profiling. In addition, subgroup analyses based on sample types suggested that blood-based multiple miRNA assays were more accurate than non-blood-based studies. In conclusion, the current meta-analysis shows that multiple miRNA assays were more accurate in diagnosing LC than single miRNA assays. However, further large-scale investigations are urgently needed to confirm our results and verify the feasibility of routine clinical utilization.

Keywords

MicroRNAs Lung cancer Diagnostic value Meta-analysis 

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29. doi:10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  2. 2.
    Akamatsu H, Mori K, Naito T, Imai H, Ono A, Shukuya T, et al. Progression-free survival at 2 years is a reliable surrogate marker for the 5-year survival rate in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy. BMC Cancer. 2014;14:18. doi:10.1186/1471-2407-14-18.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3:819–31. doi:10.1097/JTO.0b013e31818020eb.CrossRefPubMedGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. doi:10.3322/CA.2007.0010.CrossRefPubMedGoogle Scholar
  5. 5.
    Crino L, Weder W, van Meerbeeck J, Felip E. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v103–115. doi:10.1093/annonc/mdq207.CrossRefPubMedGoogle Scholar
  6. 6.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi:10.3322/caac.21166.CrossRefPubMedGoogle Scholar
  7. 7.
    Mazzone P, Jain P, Arroliga AC, Matthay RA. Bronchoscopy and needle biopsy techniques for diagnosis and staging of lung cancer. Clin Chest Med. 2002;23:137–158, ix.CrossRefPubMedGoogle Scholar
  8. 8.
    Lardinois D, Weder W, Hany TF, Kamel EM, Korom S, Seifert B, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2500–7. doi:10.1056/NEJMoa022136.CrossRefPubMedGoogle Scholar
  9. 9.
    Gohagan JK, Marcus PM, Fagerstrom RM, Pinsky PF, Kramer BS, Prorok PC, et al. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer. 2005;47:9–15. doi:10.1016/j.lungcan.2004.06.007.CrossRefPubMedGoogle Scholar
  10. 10.
    Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409. doi:10.1056/NEJMoa1102873.CrossRefPubMedGoogle Scholar
  11. 11.
    Shen J, Todd NW, Zhang H, Yu L, Lingxiao X, Mei Y, et al. Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Invest. 2011;91:579–87. doi:10.1038/labinvest.2010.194.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Ardizzoni A, Cafferata MA, Tiseo M, Filiberti R, Marroni P, Grossi F, et al. Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer. Cancer. 2006;107:2842–9. doi:10.1002/cncr.22330.CrossRefPubMedGoogle Scholar
  13. 13.
    Kulpa J, Wojcik E, Reinfuss M, Kolodziejski L. Carcinoembryonic antigen, squamous cell carcinoma antigen, CYFRA 21-1, and neuron-specific enolase in squamous cell lung cancer patients. Clin Chem. 2002;48:1931–7.PubMedGoogle Scholar
  14. 14.
    Ando S, Suzuki M, Yamamoto N, Iida T, Kimura H. The prognostic value of both neuron-specific enolase (NSE) and Cyfra21-1 in small cell lung cancer. Anticancer Res. 2004;24:1941–6.PubMedGoogle Scholar
  15. 15.
    Molina R, Auge JM, Escudero JM, Marrades R, Vinolas N, Carcereny E, et al. Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumour Biol. 2008;29:371–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Wiemer EA. The role of microRNAs in cancer: no small matter. Eur J Cancer. 2007;43:1529–44. doi:10.1016/j.ejca.2007.04.002.CrossRefPubMedGoogle Scholar
  17. 17.
    Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006;94:776–80. doi:10.1038/sj.bjc.6603023.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5:522–31. doi:10.1038/nrg1379.CrossRefPubMedGoogle Scholar
  19. 19.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8. doi:10.1038/nature03702.CrossRefPubMedGoogle Scholar
  20. 20.
    Schipper HM, Maes OC, Chertkow HM, Wang E. MicroRNA expression in Alzheimer blood mononuclear cells. Gene Regul Syst Bio. 2007;1:263–74.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426–37. doi:10.1038/nrc3066.CrossRefPubMedGoogle Scholar
  22. 22.
    Mraz M, Malinova K, Mayer J, Pospisilova S. MicroRNA isolation and stability in stored RNA samples. Biochem Biophys Res Commun. 2009;390:1–4. doi:10.1016/j.bbrc.2009.09.061.CrossRefPubMedGoogle Scholar
  23. 23.
    Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM. Systematic reviews of diagnostic test accuracy. Ann Intern Med. 2008;149:889–97.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36. doi:10.7326/0003-4819-155-8-201110180-00009.CrossRefPubMedGoogle Scholar
  25. 25.
    Deeks JJ. Systematic reviews in health care: systematic reviews of evaluations of diagnostic and screening tests. BMJ. 2001;323:157–62.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol. 2003;56:1129–35.CrossRefPubMedGoogle Scholar
  27. 27.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60. doi:10.1136/bmj.327.7414.557.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Jackson D, White IR, Thompson SG. Extending DerSimonian and Laird’s methodology to perform multivariate random effects meta-analyses. Stat Med. 2010;29:1282–97. doi:10.1002/sim.3602.CrossRefPubMedGoogle Scholar
  29. 29.
    Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58:882–93. doi:10.1016/j.jclinepi.2005.01.016.CrossRefPubMedGoogle Scholar
  30. 30.
    Xie Y, Todd NW, Liu Z, Zhan M, Fang H, Peng H, et al. Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. Lung Cancer. 2010;67:170–6. doi:10.1016/j.lungcan.2009.04.004.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Yu L, Todd NW, Xing L, Xie Y, Zhang H, Liu Z, et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer. 2010;127:2870–8. doi:10.1002/ijc.25289.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Jeong HC, Kim EK, Lee JH, Lee JM, Yoo HN, Kim JK. Aberrant expression of let-7a miRNA in the blood of non-small cell lung cancer patients. Mol Med Rep. 2011;4:383–7. doi:10.3892/mmr.2011.430.PubMedGoogle Scholar
  33. 33.
    Li Y, Li W, Ouyang Q, Hu S, Tang J. Detection of lung cancer with blood microRNA-21 expression levels in Chinese population. Oncol Lett. 2011;2:991–4. doi:10.3892/ol.2011.351.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Wei J, Liu LK, Gao W, Zhu CJ, Liu YQ, Cheng T, et al. Reduction of plasma microRNA-21 is associated with chemotherapeutic response in patients with non-small cell lung cancer. Chin J Cancer Res. 2011;23:123–8. doi:10.1007/s11670-011-0123-2.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Zheng D, Haddadin S, Wang Y, Gu LQ, Perry MC, Freter CE, et al. Plasma microRNAs as novel biomarkers for early detection of lung cancer. Int J Clin Exp Pathol. 2011;4:575–86.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Le HB, Zhu WY, Chen DD, He JY, Huang YY, Liu XG, et al. Evaluation of dynamic change of serum miR-21 and miR-24 in pre- and post-operative lung carcinoma patients. Med Oncol. 2012;29:3190–7. doi:10.1007/s12032-012-0303-z.CrossRefPubMedGoogle Scholar
  37. 37.
    Ma Y, Tian Z, Zhang W. Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J Cancer Res Clin Oncol. 2012;138:2045–50. doi:10.1007/s00432-012-1285-0.CrossRefGoogle Scholar
  38. 38.
    Wang B, Zhang Q. The expression and clinical significance of circulating microRNA-21 in serum of five solid tumors. J Cancer Res Clin Oncol. 2012;138:1659–66. doi:10.1007/s00432-012-1244-9.CrossRefPubMedGoogle Scholar
  39. 39.
    Abd-El-Fattah AA, Sadik NA, Shaker OG, Aboulftouh ML. Differential microRNAs expression in serum of patients with lung cancer, pulmonary tuberculosis, and pneumonia. Cell Biochem Biophys. 2013;67:875–84. doi:10.1007/s12013-013-9575-y.CrossRefPubMedGoogle Scholar
  40. 40.
    Ma J, Li N, Guarnera M, Jiang F. Quantification of plasma miRNAs by digital PCR for cancer diagnosis. Biomark Insights. 2013;8:127–36. doi:10.4137/bmi.s13154.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Mozzoni P, Banda I, Goldoni M, Corradi M, Tiseo M, Acampa O, et al. Plasma and EBC microRNAs as early biomarkers of non-small-cell lung cancer. Biomarkers. 2013;18:679–86. doi:10.3109/1354750x.2013.845610.CrossRefPubMedGoogle Scholar
  42. 42.
    Tang D, Shen Y, Wang M, Yang R, Wang Z, Sui A, et al. Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer. Eur J Cancer Prev. 2013;22:540–8. doi:10.1097/CEJ.0b013e32835f3be9.CrossRefPubMedGoogle Scholar
  43. 43.
    Ulivi P, Foschi G, Mengozzi M, Scarpi E, Silvestrini R, Amadori D, et al. Peripheral blood miR-328 expression as a potential biomarker for the early diagnosis of NSCLC. Int J Mol Sci. 2013;14:10332–42. doi:10.3390/ijms140510332.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Zeng XL, Zhang SY, Zheng JF, Yuan H, Wang Y. Altered miR-143 and miR-150 expressions in peripheral blood mononuclear cells for diagnosis of non-small cell lung cancer. Chin Med J (Engl). 2013;126:4510–6.Google Scholar
  45. 45.
    Gao F, Chang J, Wang H, Zhang G. Potential diagnostic value of miR-155 in serum from lung adenocarcinoma patients. Oncol Rep. 2014;31:351–7. doi:10.3892/or.2013.2830.PubMedGoogle Scholar
  46. 46.
    Shen J, Liao J, Guarnera MA, Fang H, Cai L, Stass SA, et al. Analysis of microRNAs in sputum to improve computed tomography for lung cancer diagnosis. J Thorac Oncol. 2014;9:33–40. doi:10.1097/jto.0000000000000025.CrossRefPubMedGoogle Scholar
  47. 47.
    Keller A, Leidinger P, Borries A, Wendschlag A, Wucherpfennig F, Scheffler M. miRNAs in lung cancer—studying complex fingerprints in patient’s blood cells by microarray experiments. BMC Cancer. 2009;9:353. doi:10.1186/1471-2407-9-353.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Bianchi F, Nicassio F, Marzi M, Belloni E, Dall’olio V, Bernard L, et al. A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol Med. 2011;3:495–503. doi:10.1002/emmm.201100154.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, et al. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011;108:3713–8. doi:10.1073/pnas.1100048108.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Foss KM, Sima C, Ugolini D, Neri M, Allen KE, Weiss GJ. miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. J Thorac Oncol. 2011;6:482–8. doi:10.1097/JTO.0b013e318208c785.CrossRefPubMedGoogle Scholar
  51. 51.
    Chen X, Hu Z, Wang W, Ba Y, Ma L, Zhang C, et al. Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. Int J Cancer. 2012;130:1620–8. doi:10.1002/ijc.26177.CrossRefPubMedGoogle Scholar
  52. 52.
    Hennessey PT, Sanford T, Choudhary A, Mydlarz WW, Brown D, Adai AT, et al. Serum microRNA biomarkers for detection of non-small cell lung cancer. PLoS One. 2012;7:e32307. doi:10.1371/journal.pone.0032307.PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Roa WH, Kim JO, Razzak R, Du H, Guo L, Singh R, et al. Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer. Clin Invest Med. 2012;35:E271.PubMedGoogle Scholar
  54. 54.
    Sanfiorenzo C, Ilie MI, Belaid A, Barlesi F, Mouroux J, Marquette CH, et al. Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. PLoS One. 2013;8:e54596. doi:10.1371/journal.pone.0054596.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Shen Y, Wang T, Yang T, Hu Q, Wan C, Chen L, et al. Diagnostic value of circulating microRNAs for lung cancer: a meta-analysis. Genet Test Mol Biomarkers. 2013;17:359–66. doi:10.1089/gtmb.2012.0370.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.The Department of Thoracic SurgeryShanghai Putuo District Central HospitalShanghaiChina

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