Top

Journal of Gastrointestinal Cancer

Published in:

01-03-2019 | Original Research

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

Authors: Noel Pabalan, Sutawadee Sukcharoensin, Kritiya Butthongkomvong, Hamdi Jarjanazi, Veerachai Thitapakorn

Published in: Journal of Gastrointestinal Cancer | Issue 1/2019

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 (P_interaction = 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.

Available only for authorised users

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

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

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.CrossRefPubMed

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.PubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

Title: Expression and Serum Levels of Mucin 5AC (MUC5AC) as a Biomarker for Cholangiocarcinoma: a Meta-analysis
Authors: Noel Pabalan
Sutawadee Sukcharoensin
Kritiya Butthongkomvong
Hamdi Jarjanazi
Veerachai Thitapakorn
Publication date: 01-03-2019
Publisher: Springer US
Published in: Journal of Gastrointestinal Cancer / Issue 1/2019
Print ISSN: 1941-6628
Electronic ISSN: 1941-6636
DOI: https://doi.org/10.1007/s12029-017-0032-9

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Aim

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Disregulation of miR-216a and miR-217 in Gastric Cancer and Their Clinical Significance

Hepatocellular Carcinoma Surveillance—Experience from Croatian Referral Centre for Chronic Liver Diseases

Giant Hepatic Adenoma in a 12-Year-Old Girl

Identification of Educational Gaps Among Oncologists Who Manage Patients with Pancreatic Cancer

Primary Squamous Cell Carcinoma of the Pancreas: a Case Report and Literature Review

Regulatory Fluctuation of WNT16 Gene Expression Is Associated with Human Gastric Adenocarcinoma

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage