Abstract
Objectives
Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is a transmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I–IV from benign conditions.
Methods
We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions.
Results
MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I–II) in relation to benign controls (p=0.0012 and p=0.014, respectively).
Conclusions
We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.
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Research funding: None declared.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: Sample collection was approved by the Research Ethics Boards of the University Health Network.
References
1. Torre, LA, Trabert, B, DeSantis, CE, Miller, KD, Samimi, G, Runowicz, CD, et al.. Ovarian cancer statistics, 2018. CA Cancer J Clin 2018;68:284–96. https://doi.org/10.3322/caac.21456.Search in Google Scholar PubMed PubMed Central
2. Coleman, RL, Monk, BJ, Sood, AK, Herzog, TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 2013;10:211–24. https://doi.org/10.1038/nrclinonc.2013.5.Search in Google Scholar PubMed PubMed Central
3. Kulasingam, V, Pavlou, MP, Diamandis, EP. Integrating high-throughput technologies in the quest for effective biomarkers for ovarian cancer. Nat Rev Cancer 2010;10:371–8. https://doi.org/10.1038/nrc2831.Search in Google Scholar PubMed
4. Filippou, P, Diamandis, EP. Half-century of cancer biomarkers: lessons from the past and projections for the future. J. Appl. Lab. Med. 2019;2:288–90. https://doi.org/10.1373/jalm.2016.021824.Search in Google Scholar PubMed
5. Ren, AH, Fiala, CA, Diamandis, EP. Pitfalls in cancer biomarker discovery and validation with emphasis on circulating tumor DNA. Cancer Epidemiol Biomarkers Prev 2020;29:2568–74. https://doi.org/10.1158/1055-9965.epi-20-0074.Search in Google Scholar
6. Diamandis, EP. Cancer biomarkers: can we turn recent failures into success? J Natl Cancer Inst 2010;102:1462–7. https://doi.org/10.1093/jnci/djq306.Search in Google Scholar PubMed PubMed Central
7. Diamandis, EP. The failure of protein cancer biomarkers to reach the clinic: why, and what can be done to address the problem? BMC Med 2012;10:87. https://doi.org/10.1186/1741-7015-10-87.Search in Google Scholar PubMed PubMed Central
8. Filippou, PS, Ren, AH, Korbakis, D, Dimitrakopoulos, L, Soosaipillai, A, Barak, V, et al.. Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. Clin Chem Lab Med 2018;56:1945–53. https://doi.org/10.1515/cclm-2018-0139.Search in Google Scholar PubMed
9. Filippou, P, Korbakis, D, Farkona, S, Soosaipillai, A, Karakosta, T, Diamandis, EP. A new enzyme-linked immunosorbent assay (ELISA) for human free and bound kallikrein 9. Clin Proteomics 2017;14:4. https://doi.org/10.1186/s12014-017-9140-6.Search in Google Scholar PubMed PubMed Central
10. Jonckheere, N, Skrypek, N, Van Seuningen, I. Mucins and tumor resistance to chemotherapeutic drugs. Biochim Biophys Acta 2014;1846:142–51. https://doi.org/10.1016/j.bbcan.2014.04.008.Search in Google Scholar PubMed
11. Dhanisha, SS, Guruvayoorappan, C, Drishya, S, Abeesh, P. Mucins: structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets. Crit Rev Oncol Hematol 2018;122:98–122. https://doi.org/10.1016/j.critrevonc.2017.12.006.Search in Google Scholar PubMed
12. Bhatia, R, Gautam, SK, Cannon, A, Thompson, C, Hall, BR, Aithal, A, et al.. Cancer-associated mucins: role in immune modulation and metastasis. Cancer Metastasis Rev 2019;38:223–36. https://doi.org/10.1007/s10555-018-09775-0.Search in Google Scholar PubMed PubMed Central
13. Singh, AP, Senapati, S, Ponnusamy, MP, Jain, M, Lele, SM, Davis, JS, et al.. Clinical potential of mucins in diagnosis, prognosis, and therapy of ovarian cancer. Lancet Oncol 2008;9:1076–85. https://doi.org/10.1016/s1470-2045(08)70277-8.Search in Google Scholar PubMed PubMed Central
14. Yin, BW, Dnistrian, A, Lloyd, KO. Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Int J Cancer 2002;98:737–40. https://doi.org/10.1002/ijc.10250.Search in Google Scholar PubMed
15. Cramer, DW, Bast, RCJr., Berg, CD, Diamandis, EP, Godwin, AK, Hartge, P, et al.. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res (Phila) 2011;4:365–74. https://doi.org/10.1158/1940-6207.capr-10-0195.Search in Google Scholar
16. Chauhan, SC, Singh, AP, Ruiz, F, Johansson, SL, Jain, M, Smith, LM, et al.. Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125). Mod Pathol 2006;19:1386–94. https://doi.org/10.1038/modpathol.3800646.Search in Google Scholar PubMed
17. Maher, DM, Gupta, BK, Nagata, S, Jaggi, M, Chauhan, SC. Mucin 13: structure, function, and potential roles in cancer pathogenesis. Mol Cancer Res 2011;9:531–7. https://doi.org/10.1158/1541-7786.mcr-10-0443.Search in Google Scholar PubMed PubMed Central
18. Williams, SJ, Wreschner, DH, Tran, M, Eyre, HJ, Sutherland, GR, McGuckin, MA. Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem 2001;276:18327–36. https://doi.org/10.1074/jbc.m008850200.Search in Google Scholar
19. Shimamura, T, Ito, H, Shibahara, J, Watanabe, A, Hippo, Y, Taniguchi, H, et al.. Overexpression of MUC13 is associated with intestinal-type gastric cancer. Cancer Sci 2005;96:265–73. https://doi.org/10.1111/j.1349-7006.2005.00043.x.Search in Google Scholar PubMed
20. Khan, S, Ebeling, MC, Zaman, MS, Sikander, M, Yallapu, MM, Chauhan, N, et al.. MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. Oncotarget 2014;5:7599–609. https://doi.org/10.18632/oncotarget.2281.Search in Google Scholar PubMed PubMed Central
21. Sheng, Y, Ng, CP, Lourie, R, Shah, ET, He, Y, Wong, KY, et al.. MUC13 overexpression in renal cell carcinoma plays a central role in tumor progression and drug resistance. Int J Cancer 2017;140:2351–63. https://doi.org/10.1002/ijc.30651.Search in Google Scholar PubMed
22. Sheng, YH, Wong, KY, Seim, I, Wang, R, He, Y, Wu, A, et al.. MUC13 promotes the development of colitis-associated colorectal tumors via beta-catenin activity. Oncogene 2019;38:7294–310. https://doi.org/10.1038/s41388-019-0951-y.Search in Google Scholar PubMed
23. Chauhan, SC, Vannatta, K, Ebeling, MC, Vinayek, N, Watanabe, A, Pandey, KK, et al.. Expression and functions of transmembrane mucin MUC13 in ovarian cancer. Cancer Res 2009;69:765–74. https://doi.org/10.1158/0008-5472.can-08-0587.Search in Google Scholar
24. Linden, SK, Sutton, P, Karlsson, NG, Korolik, V, McGuckin, MA. Mucins in the mucosal barrier to infection. Mucosal Immunol 2008;1:183–97. https://doi.org/10.1038/mi.2008.5.Search in Google Scholar PubMed PubMed Central
25. Sheng, YH, Lourie, R, Linden, SK, Jeffery, PL, Roche, D, Tran, TV, et al.. The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis. Gut 2011;60:1661–70. https://doi.org/10.1136/gut.2011.239194.Search in Google Scholar PubMed
26. Sheng, YH, Triyana, S, Wang, R, Das, I, Gerloff, K, Florin, TH, et al.. MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli. Mucosal Immunol 2013;6:557–68. https://doi.org/10.1038/mi.2012.98.Search in Google Scholar PubMed
27. LaMonte, GM, Orjuela-Sanchez, P, Calla, J, Wang, LT, Li, S, Swann, J, et al.. Dual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection. Nat Commun 2019;10:488. https://doi.org/10.1038/s41467-019-08349-0.Search in Google Scholar PubMed PubMed Central
28. Chauhan, SC, Kumar, D, Jaggi, M. Mucins in ovarian cancer diagnosis and therapy. J Ovarian Res 2009;2:21. https://doi.org/10.1186/1757-2215-2-21.Search in Google Scholar PubMed PubMed Central
29. Crawford, SM, Evans, C. Outcome of elevated CA125 values from primary care following implementation of ovarian cancer guidelines. Fam Pract 2017;35:199–202. https://doi.org/10.1093/fampra/cmx096.Search in Google Scholar PubMed
30. Sung, HY, Park, AK, Ju, W, Ahn, JH. Overexpression of mucin 13 due to promoter methylation promotes aggressive behavior in ovarian cancer cells. Yonsei Med J 2014;55:1206–13. https://doi.org/10.3349/ymj.2014.55.5.1206.Search in Google Scholar PubMed PubMed Central
31. Micha, JP, Goldstein, BH, Rettenmaier, MA, Brown, JV3rd, John, CR, Markman, M. Clinical utility of CA-125 for maintenance therapy in the treatment of advanced stage ovarian carcinoma. Int J Gynecol Cancer 2009;19:239–41. https://doi.org/10.1111/igc.0b013e31819c55c9.Search in Google Scholar PubMed
32. Shah, CA, Lowe, KA, Paley, P, Wallace, E, Anderson, GL, McIntosh, MW, et al.. Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125. Cancer Epidemiol Biomarkers Prev 2009;18:1365–72. https://doi.org/10.1158/1055-9965.epi-08-1034.Search in Google Scholar
33. Sarojini, S, Tamir, A, Lim, H, Li, S, Zhang, S, Goy, A, et al.. Early detection biomarkers for ovarian cancer. J Oncol 2012;2012:709049. https://doi.org/10.1155/2012/709049.Search in Google Scholar PubMed PubMed Central
34. Duffy, MJ, Bonfrer, JM, Kulpa, J, Rustin, GJ, Soletormos, G, Torre, GC, et al.. CA125 in ovarian cancer: European Group on tumor markers guidelines for clinical use. Int J Gynecol Cancer 2005;15:679–91. https://doi.org/10.1111/j.1525-1438.2005.00130.x.Search in Google Scholar PubMed
35. Nolen, BM, Lokshin, AE. Biomarker testing for ovarian cancer: clinical utility of multiplex assays. Mol Diagn Ther 2013;17:139–46. https://doi.org/10.1007/s40291-013-0027-6.Search in Google Scholar PubMed PubMed Central
36. Moss, EL, Hollingworth, J, Reynolds, TM. The role of CA125 in clinical practice. J Clin Pathol 2005;58:308–12. https://doi.org/10.1136/jcp.2004.018077.Search in Google Scholar PubMed PubMed Central
37. Leung, F, Bernardini, MQ, Brown, MD, Zheng, Y, Molina, R, Bast, RCJr., et al.. Validation of a novel biomarker panel for the detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev 2016;25:1333–40. https://doi.org/10.1158/1055-9965.epi-15-1299.Search in Google Scholar PubMed PubMed Central
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2022-0491).
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