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Expression and Serum Levels of Mucin 5AC (MUC5AC) as a Biomarker for Cholangiocarcinoma: a Meta-analysis

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Abstract

Aim

The potential of biomarkers in detecting early cholangiocarcinoma (CCA) is facilitated by examining CCA-associated proteins from primary studies. One such protein is mucin 5AC (MUC5AC) but inconsistency of reported associations between its expression/serum levels and CCA prompts a meta-analysis to obtain more precise estimates.

Methods

A literature search yielded 17 included articles where multiple data in some raised the number of studies to 22. We calculated pooled odds ratios (OR) and 95% confidence intervals from negative and positive readings of MUC5AC levels. Data were subgrouped by ethnicity, detection method, sample source, and cancer type.

Results

Outcome in the overall analysis was non-significant but those in the subgroups were. Thus, significant associations (P < 0.001) indicating high MUC5AC levels were found in three subgroups: (i) Thai (OR 8.32) and (ii) serum (OR 4.52). Heterogeneity of these two outcomes (I2 = 90–93%) was erased with outlier treatment (I2 = 0%) which also modulated the pooled effects (OR 2.48–2.59). (iii) Immunoblot (OR 2.61) had low initial heterogeneity (I2 = 2%). Robustness and significant tests for interaction (Pinteraction = 0.01–0.02) improved MUC5AC associations with CCA in the Thai population.

Conclusions

Our pooled effect findings target the biomarker potential of MUC5AC to the Thai population.

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References

  1. Blechacz BR, Gores GJ. Cholangiocarcinoma. Clin Liver Dis. 2008;12(1):131–150, ix. https://doi.org/10.1016/j.cld.2007.11.003.

    Article  PubMed  Google Scholar 

  2. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54(1):173–84. https://doi.org/10.1002/hep.24351.

    Article  CAS  PubMed  Google Scholar 

  3. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis. 2004;24(02):139–54. https://doi.org/10.1055/s-2004-828891.

    Article  CAS  PubMed  Google Scholar 

  4. Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WM, Taylor-Robinson SD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1–9.

    PubMed  PubMed Central  Google Scholar 

  5. Bonney GK, Craven RA, Prasad R, Melcher AF, Selby PJ, Banks RE. Circulating markers of biliary malignancy: opportunities in proteomics? Lancet Oncol. 2008;9(2):149–58. https://doi.org/10.1016/S1470-2045(08)70027-5.

    Article  CAS  PubMed  Google Scholar 

  6. Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, et al. Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience. Am J Gastroenterol. 2001;96(4):1164–9. https://doi.org/10.1111/j.1572-0241.2001.03696.x.

    Article  CAS  PubMed  Google Scholar 

  7. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, Thomas HC. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002;37(6):806–13. https://doi.org/10.1016/S0168-8278(02)00297-0.

    Article  PubMed  Google Scholar 

  8. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24(02):115–25. https://doi.org/10.1055/s-2004-828889.

    Article  PubMed  Google Scholar 

  9. Sirica AE. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology. 2005;41(1):5–15. https://doi.org/10.1002/hep.20537.

    Article  PubMed  Google Scholar 

  10. Sasaki M, Nakanuma Y, Kim YS. Expression of apomucins in the intrahepatic biliary tree in hepatolithiasis differs from that in normal liver and extrahepatic biliary obstruction. Hepatology. 1998;27(1):54–61. https://doi.org/10.1002/hep.510270110.

    Article  CAS  PubMed  Google Scholar 

  11. Buisine MP, Devisme L, Maunoury V, Deschodt E, Gosselin B, Copin MC, et al. Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach: a relationship to gastric carcinoma. J Histochem Cytochem. 2000;48(12):1657–66. https://doi.org/10.1177/002215540004801209.

    Article  CAS  PubMed  Google Scholar 

  12. Higashi M, Yonezawa S, Ho JJ, Tanaka S, Irimura T, Kim YS, et al. Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma. Hepatology. 1999;30(6):1347–55. https://doi.org/10.1002/hep.510300609.

    Article  CAS  PubMed  Google Scholar 

  13. Lee KT, Liu TS. Altered mucin gene expression in stone-containing intrahepatic bile ducts and cholangiocarcinomas. Dig Dis Sci. 2001;46(10):2166–72. https://doi.org/10.1023/A:1011906830301.

    Article  CAS  PubMed  Google Scholar 

  14. Moschovis D, Bamias G, Delladetsima I. Mucins in neoplasms of pancreas, ampulla of Vater and biliary system. World J Gastrointest Oncol. 2016;8(10):725–34. https://doi.org/10.4251/wjgo.v8.i10.725.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Guyonnet Duperat V, Audie JP, Debailleul V, Laine A, Buisine MP, Galiegue-Zouitina S, et al. Characterization of the human mucin gene MUC5AC: a consensus cysteine-rich domain for 11p15 mucin genes? Biochem J. 1995;305(Pt 1):211–9. https://doi.org/10.1042/bj3050211.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rakha EA, Boyce RW, Abd El-Rehim D, Kurien T, Green AR, Paish EC, et al. Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Modern Pathol : Off J U S Canadian Acad Pathol Inc. 2005;18(10):1295–304. https://doi.org/10.1038/modpathol.3800445.

    Article  CAS  Google Scholar 

  17. Yonezawa S, Sato E. Expression of mucin antigens in human cancers and its relationship with malignancy potential. Pathol Int. 1997;47(12):813–30. https://doi.org/10.1111/j.1440-1827.1997.tb03713.x.

    Article  CAS  PubMed  Google Scholar 

  18. Farina A, Dumonceau JM, Lescuyer P. Proteomic analysis of human bile and potential applications for cancer diagnosis. Expert Rev Proteomics. 2009;6(3):285–301. https://doi.org/10.1586/epr.09.12.

    Article  CAS  PubMed  Google Scholar 

  19. Yeh TS, Tseng JH, Chen TC, Liu NJ, Chiu CT, Jan YY, et al. Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions. Hepatology. 2005;42(3):657–64. https://doi.org/10.1002/hep.20837.

    Article  PubMed  Google Scholar 

  20. 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(8):529–36. https://doi.org/10.7326/0003-4819-155-8-201110180-00009.

    Article  PubMed  Google Scholar 

  21. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  22. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. https://doi.org/10.1016/0197-2456(86)90046-2.

    Article  CAS  PubMed  Google Scholar 

  23. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127(9):820–6. https://doi.org/10.7326/0003-4819-127-9-199711010-00008.

    Article  CAS  PubMed  Google Scholar 

  24. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. https://doi.org/10.1002/sim.1186.

    Article  PubMed  Google Scholar 

  25. Wallace B, Dahabreh CJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the gap between methodologists and end-users: R as a computational back-end. J Stat Softw. 2012;49:1–15.

    Article  Google Scholar 

  26. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med. 1988;7(8):889–94. https://doi.org/10.1002/sim.4780070807.

    Article  CAS  PubMed  Google Scholar 

  27. Pabalan N, Kunjantarachot A, Ruangpratheep C, Jarjanazi H, Christofolini DM, Barbosa CP, et al. Potential of RASSF1A promoter methylation as biomarker for endometrial cancer: a systematic review and meta-analysis. Gynecol Oncol. 2017;146(3):603–8. https://doi.org/10.1016/j.ygyno.2017.06.017.

    Article  CAS  PubMed  Google Scholar 

  28. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60. https://doi.org/10.1136/bmj.327.7414.557.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–29. https://doi.org/10.1016/S0895-4356(00)00242-0.

    Article  CAS  PubMed  Google Scholar 

  30. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101. https://doi.org/10.2307/2533446.

    Article  CAS  PubMed  Google Scholar 

  31. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007;176(8):1091–6. https://doi.org/10.1503/cmaj.060410.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https://doi.org/10.1186/2046-4053-4-1.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Guedj N, Zhan Q, Perigny M, Rautou PE, Degos F, Belghiti J, et al. Comparative protein expression profiles of hilar and peripheral hepatic cholangiocarcinomas. J Hepatol. 2009;51(1):93–101. https://doi.org/10.1016/j.jhep.2009.03.017.

    Article  CAS  PubMed  Google Scholar 

  34. Lee MJ, Lee HS, Kim WH, Choi Y, Yang M. Expression of mucins and cytokeratins in primary carcinomas of the digestive system. Modern Pathol : Off J U S Canadian Acad Pathol Inc. 2003;16(5):403–10. https://doi.org/10.1097/01.MP.0000067683.84284.66.

    Article  Google Scholar 

  35. Abe T, Amano H, Shimamoto F, Hattori M, Kuroda S, Kobayashi T, et al. Prognostic evaluation of mucin-5AC expression in intrahepatic cholangiocarcinoma, mass-forming type, following hepatectomy. Eur J Surg Oncol. 2015;41(11):1515–21. https://doi.org/10.1016/j.ejso.2015.07.006.

    Article  CAS  PubMed  Google Scholar 

  36. Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Iguchi T, Taketomi A, et al. Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression. Hum Pathol. 2007;38(12):1819–25. https://doi.org/10.1016/j.humpath.2007.04.016.

    Article  CAS  PubMed  Google Scholar 

  37. Aishima S, Kuroda Y, Nishihara Y, Taguchi K, Taketomi A, Maehara Y, et al. Gastric mucin phenotype defines tumour progression and prognosis of intrahepatic cholangiocarcinoma: gastric foveolar type is associated with aggressive tumour behaviour. Histopathology. 2006;49(1):35–44. https://doi.org/10.1111/j.1365-2559.2006.02414.x.

    Article  CAS  PubMed  Google Scholar 

  38. Bamrungphon W, Prempracha N, Bunchu N, Rangdaeng S, Sandhu T, Srisukho S, et al. A new mucin antibody/enzyme-linked lectin-sandwich assay of serum MUC5AC mucin for the diagnosis of cholangiocarcinoma. Cancer Lett. 2007;247(2):301–8. https://doi.org/10.1016/j.canlet.2006.05.007.

    Article  CAS  PubMed  Google Scholar 

  39. Boonla C, Sripa B, Thuwajit P, Cha-On U, Puapairoj A, Miwa M, et al. MUC1 and MUC5AC mucin expression in liver fluke-associated intrahepatic cholangiocarcinoma. World J Gastroenterol. 2005;11(32):4939–46. https://doi.org/10.3748/wjg.v11.i32.4939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Boonla C, Wongkham S, Sheehan JK, Wongkham C, Bhudhisawasdi V, Tepsiri N, et al. Prognostic value of serum MUC5AC mucin in patients with cholangiocarcinoma. Cancer. 2003;98(7):1438–43. https://doi.org/10.1002/cncr.11652.

    Article  CAS  PubMed  Google Scholar 

  41. Danese E, Ruzzenente O, Ruzzenente A, Iacono C, Bertuzzo F, Gelati M, et al. Assessment of bile and serum mucin5AC in cholangiocarcinoma: diagnostic performance and biologic significance. Surgery. 2014;156(5):1218–24. https://doi.org/10.1016/j.surg.2014.05.006.

    Article  PubMed  Google Scholar 

  42. Lok T, Chen L, Lin F, Wang HL. Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma. Hum Pathol. 2014;45(2):394–400. https://doi.org/10.1016/j.humpath.2013.10.004.

    Article  CAS  PubMed  Google Scholar 

  43. Mall AS, Tyler MG, Ho SB, Krige JE, Kahn D, Spearman W, et al. The expression of MUC mucin in cholangiocarcinoma. Pathol Res Pract. 2010;206(12):805–9. https://doi.org/10.1016/j.prp.2010.08.004.

    Article  CAS  PubMed  Google Scholar 

  44. Onoe S, Shimoyama Y, Ebata T, Yokoyama Y, Igami T, Sugawara G, et al. Clinicopathological significance of mucin production in patients with papillary cholangiocarcinoma. World J Surg. 2015;39(5):1177–84. https://doi.org/10.1007/s00268-014-2923-2.

    Article  PubMed  Google Scholar 

  45. Park SY, Roh SJ, Kim YN, Kim SZ, Park HS, Jang KY, et al. Expression of MUC1, MUC2, MUC5AC and MUC6 in cholangiocarcinoma: prognostic impact. Oncol Rep. 2009;22(3):649–57.

    CAS  PubMed  Google Scholar 

  46. Ruzzenente A, Iacono C, Conci S, Bertuzzo F, Salvagno G, Ruzzenente O, et al. A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC). Surgery. 2014;155(4):633–9. https://doi.org/10.1016/j.surg.2013.12.003.

    Article  PubMed  Google Scholar 

  47. Wongkham S, Sheehan JK, Boonla C, Patrakitkomjorn S, Howard M, Kirkham S, et al. Serum MUC5AC mucin as a potential marker for cholangiocarcinoma. Cancer Lett. 2003;195(1):93–9. https://doi.org/10.1016/S0304-3835(02)00691-2.

    Article  CAS  PubMed  Google Scholar 

  48. Matull WR, Andreola F, Loh A, Adiguzel Z, Deheragoda M, Qureshi U, et al. MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer. Br J Cancer. 2008;98(10):1675–81. https://doi.org/10.1038/sj.bjc.6604364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Silsirivanit A, Araki N, Wongkham C, Pairojkul C, Narimatsu Y, Kuwahara K, et al. A novel serum carbohydrate marker on mucin 5AC: values for diagnostic and prognostic indicators for cholangiocarcinoma. Cancer. 2011;117(15):3393–403. https://doi.org/10.1002/cncr.25912.

    Article  CAS  PubMed  Google Scholar 

  50. Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J Biomed Inform. 2014;48:193–204. https://doi.org/10.1016/j.jbi.2014.02.013.

    Article  PubMed  Google Scholar 

  51. Xuan J, Li J, Zhou Z, Zhou R, Xu H, Wen W. The diagnostic performance of serum MUC5AC for cholangiocarcinoma: a systematic review and meta-analysis. Medicine. 2016;95(24):e3513. https://doi.org/10.1097/MD.0000000000003513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Babu SD, Jayanthi V, Devaraj N, Reis CA, Devaraj H. Expression profile of mucins (MUC2, MUC5AC and MUC6) in Helicobacter pylori infected pre-neoplastic and neoplastic human gastric epithelium. Mol Cancer. 2006;5(1):10. https://doi.org/10.1186/1476-4598-5-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sasaki M, Nakanuma Y, Kim YS. Characterization of apomucin expression in intrahepatic cholangiocarcinomas and their precursor lesions: an immunohistochemical study. Hepatology. 1996;24(5):1074–8. https://doi.org/10.1002/hep.510240516.

    Article  CAS  PubMed  Google Scholar 

  54. Sawanyawisuth K, Silsirivanit A, Kunlabut K, Tantapotinan N, Vaeteewoottacharn K, Wongkham S. A novel carbohydrate antigen expression during development of Opisthorchis viverrini-associated cholangiocarcinoma in golden hamster: a potential marker for early diagnosis. Parasitol Int. 2012;61(1):151–4. https://doi.org/10.1016/j.parint.2011.07.013.

    Article  CAS  PubMed  Google Scholar 

  55. Hanash SM, Pitteri SJ, Faca VM. Mining the plasma proteome for cancer biomarkers. Nature. 2008;452(7187):571–9. https://doi.org/10.1038/nature06916.

    Article  CAS  PubMed  Google Scholar 

  56. Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93(14):1054–61. https://doi.org/10.1093/jnci/93.14.1054.

    Article  CAS  PubMed  Google Scholar 

  57. Lau SK, Weiss LM, Chu PG. Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study. Am J Clin Pathol. 2004;122(1):61–9. https://doi.org/10.1309/9R6673QEC06D86Y4.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Chulabhorn International College of Medicine, Thammasat University, Khlong Luang, Pathum Thani, Thailand

    Noel Pabalan, Sutawadee Sukcharoensin & Veerachai Thitapakorn

  2. Medical Oncology Unit, Udonthani Cancer Hospital, Udonthani, Thailand

    Kritiya Butthongkomvong

  3. Environmental Monitoring and Reporting Branch, Ontario Ministry of the Environment and Climate Change, 125 Resources Road, Toronto, ON, Canada

    Hamdi Jarjanazi

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  1. Noel Pabalan
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Correspondence to Noel Pabalan.

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Pabalan, N., Sukcharoensin, S., Butthongkomvong, K. et al. Expression and Serum Levels of Mucin 5AC (MUC5AC) as a Biomarker for Cholangiocarcinoma: a Meta-analysis. J Gastrointest Canc 50, 54–61 (2019). https://doi.org/10.1007/s12029-017-0032-9

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