Abstract
CA 125 also known as mucin 16 or MUC16 is a large membrane glycoprotein belonging to the wide mucin family, encoded by the homonymous MUC16 gene. Following its discovery in the blood of some patients with specific types of cancers or other benign conditions, CA125 has found application as a tumor marker of ovarian cancer. Thirty years after its discovery, use of CA 125 is still FDA-recommended to monitor response to therapy in patients with epithelial ovarian cancer and to detect residual or recurrent disease in patients who have undergone first-line therapy and would be considered for second-look procedures. However, due to its limited specificity and sensitivity, CA 125 alone cannot still be an ideal biomarker. Increased clinical performance, in terms of better sensitivity and specificity in identifying epithelial ovarian cancer relapse, has been obtained by combined use of CA 125 with HE4, another ovarian cancer marker recently introduced in clinical use. Significant advancements have been achieved more recently, due to the introduction of FDA-approved ROMA and OVA1 algorithms to evaluate the risk of ovarian cancer for patients with a pelvic mass.
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References
Senapati S, Das S, Batra SK (2010) Mucin-interacting proteins: from function to therapeutics. Trends Biochem Sci 35:236–245
Rose MC, Voynow JA (2006) Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86:245–278
Gendler SJ, Burchell JM, Duhig T et al (1987) Cloning of partial cDNA encoding differentiation and tumor-associated mucin glycoproteins expressed by human mammary epithelium. Proc Natl Acad Sci U S A 84:6060–6064
Gupta R, Jentoft N (1989) Subunit structure of porcine submaxillary mucin. Biochemistry 28:6114–6121
Timpte CS, Eckhardt AE, Abernethy JL, Hill RL (1988) Porcine submaxillary gland apomucin contains tandemly repeated, identical sequences of 81 residues. J Biol Chem 263:1081–1088
Lang T, Hansson GC, Samuelsson T (2007) Gel-forming mucins appeared early in metazoan evolution. Proc Natl Acad Sci U S A 104:16209–16214
Hollingsworth MA, Swanson BJ (2004) Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4:45–60
Chen Y, Zhao YH, Kalaslavadi TB et al (2004) Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues. Am J Respir Cell Mol Biol 30:155–165
Corfield AP (2015) Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim Biophys Acta 1850:236–252
Kufe DW (2009) Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 9:874–885
Carraway KL, Ramsauer VP, Haq B, Carothers Carraway CA (2003) Cell signaling through membrane mucins. Bioessays 25:66–71
Jepson S, Komatsu M, Haq B et al (2002) Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways. Oncogene 21:7524–7532
Levitin F, Stern O, Weiss M et al (2005) The MUC1 SEA module is a self-cleaving domain. J Biol Chem 280:33374–33386
Gendler SJ, Spicer AP (1995) Epithelial mucin genes. Annu Rev Physiol 57:607–634
Singh AP, Moniaux N, Chauhan SC et al (2004) Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Res 64:622–630
Chan AK, Lockhart DC, von Bernstorff W (1999) Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation. Int J Cancer 82:721–726
Argueso P, Guzman-Aranguez A, Mantelli F et al (2009) Association of cell surface mucins with galectin-3 contributes to the ocular surface epithelial barrier. J Biol Chem 284:23037–23045
Seelenmeyer C, Wegehingel S, Lechner J, Nickel W (2003) The cancer antigen CA125 represents a novel counter receptor for galectin-1. J Cell Sci 116:1305–1318
Patankar MS, Jing Y, Morrison JC et al (2005) Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol Oncol 99:704–713
Belisle JA, Gubbels JA, Raphael CA et al (2007) Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 122:418–429
Gubbels JA, Belisle J, Onda M et al (2006) Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer 5:50
Rump A, Morikawa Y, Tanaka M (2004) Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem 279:9190–9198
Bergan L, Gross JA, Nevin B et al (2007) Development and in vitro validation of antimesothelin biobodies that prevent CA125/Mesothelin-dependent cell attachment. Cancer Lett 255:263–274
Kaneko O, Gong L, Zhang J et al (2009) A binding domain on mesothelin for CA125/MUC16. J Biol Chem 284:3739–3749
Bast RC Jr, Feeney M, Lazarus H et al (1981) Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 68:1331–1337
Bast RC Jr, Klug TL, St. John E et al (1983) A radio-immunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883
Bast RC Jr, Xu FJ, Yu YH et al (1998) CA 125: the past and the future. Int J Biol Markers 13:179–187
Sturgeon CM, Duffy MJ, Stenman UH et al (2008) National academy of clinical biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 54:e11–e79
Davelaar EM, van Kamp GJ, Verstraeten RA, Kenemans P (1998) Comparison of seven immunoassays for the quantification of CA 125 antigen in serum. Clin Chem 44:1417–1422
Shih Ie M, Sokoll L, Chan DW (2002) Ovarian cancer. In: Diamandis EP, Fritsche HA, Lilja H, Chan DW, Schwartz MK (eds) Tumor markers: physiology, pathobiology, technology and clinical applications. AACC Press, Washington, DC, pp 239–252
Masahashi T, Matsuzawa K, Ohsawa M et al (1988) Serum CA 125 levels in patients with endometriosis: changes of CA 125 levels during menstruation. Obstet Gynecol 72:328
Bergmann JF, Beaugrand M, Labadie H et al (1986) CA 125 (ovarian tumour-associated antigen) in ascitic liver diseases. Clin Chim Acta 155:163
Molina R, Ballesta AM, Casals E et al (1984) Value of CA 125 antigen as tumor marker: preliminary results. In: Peeters H (ed) Protides of the biological fluids. Proceedings of the 32nd Colloquium, Brussels, p 613
Ruibal A, Encabo G, Miralles EM et al (1984) CA 125 seric levels in non ovarian pathologies. In: Peeters H (ed) Protides of the biological fluids. Proceedings of the 32nd Colloquium, Brussels, p 605
Giudice LC, Jacobs A, Pineda J et al (1986) Serum levels of CA 125 in patients with endometriosis: a preliminary report. Fertil Steril 45(6):876
Malkasian GD Jr, Podratz KC, Stanhope CR et al (1986) CA 125 in gynecologic practice. Am J Obstet Gynecol 155:515
Haga Y, Sakamoto K, Egami H et al (1986) Evaluation of serum CA 125 values in healthy individuals and pregnant women. Am J Med Sci 292:25
Halila H, Stenman UH, Seppala M (1986) Ovarian cancer antigen CA 125. Levels in pelvic inflammatory disease and pregnancy. Cancer 57:1327
Pittaway DE, Fayez JA, Douglas JW (1987) Serum CA 125 in the evaluation of benign adnexal cysts. Am J Obstet Gynecol 157:1426
Niloff JM, Knapp RC, Schaetzl E et al (1984) CA 125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol 64:703
Haga Y, Sakamoto K, Egami H et al (1986) Clinical significance of serum CA 125 values in patients with cancers of the digestive system. Am J Med Sci 292:30
Duk JM, Aalders JG, Fleuren GJ et al (1986) CA 125: a useful marker in endometrial carcinoma. Am J Obstet Gynecol 155:1097
Bertholf RL, Johannsen L, Guy B (2002) False elevation of serum CA-125 level caused by human anti-mouse antibodies. Ann Clin Lab Sci 32:414–418
Boerman OC, Segers MF, Poels LG et al (1990) Heterophilic antibodies in human sera causing falsely increased results in the CA 125 immunofluorometric assay. Clin Chem 36:888–891
Young RH, Clement PB, Scully RE, Sternberg SS (1999) The ovary: diagnostic surgical pathology, vol 3. Lippincott Williams & Wilkins, Philadelphia, pp 2307–2394
Scully RE (ed) (1999) Histological typing of ovarian tumours, 2nd edn, Sobin LH and pathologists in 5 countries, collaborators. Springer, New York, p 136
Seidman JD, Horkayne-Szakaly I, Haiba M et al (2004) The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 23:41–44
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J et al (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403
Fleisher M, Dnistrian A, Sturgeon C, Lamerz R, Witliff J (2002) Practice guidelines and recommendations for use of tumor markers in the clinic. Tumor markers: physiology, pathobiology, technology and clinical applications. AACC Press, Washington, DC, pp 33–63
NCCN [National Comprehensive Cancer Network] Clinical Practice Guidelines in Oncology (2008) Ovarian cancer. Version 1. http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed Nov 2008
Vasey PA, Herrstedt J, Jelic S (2005) ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of epithelial ovarian carcinoma. Ann Oncol 16(Suppl 1):i13–i15
Skates SJ, Xu FJ, Yu YH et al (1995) Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers. Cancer 76:2004–2010
Bast RC Jr, Brewer M, Zou C et al (2007) Prevention and early detection of ovarian cancer: mission impossible? Recent Results Cancer Res 174:91–100
Bast RC Jr, Urban N, Shridhar V et al (2002) Early detection of ovarian cancer: promise and reality. Cancer Treat Res 107:61–97
Zhang Z, Bast RC Jr, Yu Y et al (2004) Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64:5882–5890
Kobayashi H, Yamada Y, Sado T et al (2008) A randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J Gynecol Cancer 18:414–420
Buys SS, Partridge E, Black A et al (2011) Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA 305:2295–2303
Menon U, Gentry-Maharaj A, Hallett R et al (2009) Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 10:327–340
Menon U, Griffin M, Gentry-Maharaj A (2014) Ovarian cancer screening-current status, future directions. Gynecol Oncol 132:490–495
Duffy MJ, Bonfrer JM, Kulpa J et al (2005) CA125 in ovarian cancer: European group on tumor markers guidelines for clinical use. Int J Gynecol Cancer 15:679–691
Gronlund B, Hogdall C, Hilden J et al (2004) Should CA-125 response criteria be preferred to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma? J Clin Oncol 22:4051–4058
Su Z, Graybill WS, Zhu Y (2013) Detection and monitoring of ovarian cancer. Clin Chim Acta 415:341–345
Rustin GJ, Vergote I, Eisenhauer E et al (2011) Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 21:419–423
Gadducci A, Fuso L, Cosio S et al (2009) Are surveillance procedures of clinical benefit for patients treated for ovarian cancer?: a retrospective Italian multicentric study. Int J Gynecol Cancer 19:367–374
Nadal RM, Ojeda BM, Artigas V et al (2006) Stratification of the normal range of CA-125 after chemotherapy as a predictive factor in carcinoma of the ovary. J Clin Oncol 24:270 s (suppl; abstr 5059)
Tanabe H, Katsumata N, Matsumoto K et al (2006) CA-125 nadir as a prognostic factor in advanced ovarian carcinoma: a retrospective study of 84 patients achieving clinical CR. J Clin Oncol 24:270 s (suppl; abstr 5060)
Markman M, Liu PY, Rothenberg ML et al (2006) Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol 24:1454–1458
Liu PY, Alberts DS, Monk BJ et al (2007) An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. J Clin Oncol 25:3615–3620
Prat A, Parera M, Peralta S et al (2008) Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer. Ann Oncol 19:327–331
Clauss A, Lilja H, Lundwall A (2002) A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein. Biochem J 368:233–242
Hellstrom I, Raycraft J, Hayden-Ledbetter M et al (2003) The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res 63:3695–3700
Li J, Dowdy S, Tipton T et al (2009) HE4 as a biomarker for ovarian and endometrial cancer management. Expert Rev Mol Diagn 9:555–566
Bingle L, Singleton V, Bingle CD (2002) The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene 21:2768–2773
Ferraro S, Schiumarini D, Panteghini M (2015) Human epididymis protein 4: factors of variation. Clin Chim Acta 438:171–177
Moore RG, Miller MC, Eklund EE (2012) Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet Gynecol 206(349):e1–e7
Huhtinen K, Suvitie P, Hiissa J et al (2009) Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer 100:1315–1319
Anastasi E, Marchei GG, Viggiani V et al (2010) HE4: a new potential early biomarker for the recurrence of ovarian cancer. Tumour Biol 31:113–119
Hynninen J, Auranen A, Dean K et al (2011) Serum HE4 profile during primary chemotherapy of epithelial ovarian cancer. Int J Gynecol Cancer 21:1573–1578
Manganaro L, Michienzi S, Vinci V et al (2013) Serum HE4 levels combined with CE CT imaging improve the management of monitoring women affected by epithelial ovarian cancer. Oncol Rep 30:2481–2487
ROMAâ„¢ (HE4 EIA + ARCHITECT CA 125 IITM) Prescribing Information (2011) Fujirebio Diagnostics, Inc.
Kalapotharakos G, Asciutto C, Henic E et al (2012) High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer. J Ovarian Res 5:20
Sandri MT, Bottari F, Franchi D et al (2013) Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome. Gynecol Oncol 128:233–238
Wang J, Gao J, Yao H et al (2014) Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour Biol 35:6127–6138
Chudecka-Głaz AM (2015) ROMA, an algorithm for ovarian cancer. Clin Chim Acta 440:143–151
Zhang Z, Chan DW (2010) The road from discovery to clinical diagnostics: lessons learned from the first FDA-cleared in vitro diagnostic multivariate index assay of proteomic biomarkers. Cancer Epidemiol Biomarkers Prev 19:2995–2999
Fung ET (2010) A recipe for proteomics diagnostic test development: the OVA1 test, from biomarker discovery to FDA clearance. Clin Chem 56:327–329
Ueland FR, Desimone CP, Seamon LG et al (2011) Effectiveness of a multivariate index assay in the preoperative assessment of ovarian tumors. Obstet Gynecol 117:1289–1297
Bristow RE, Smith A, Zhang Z et al (2013) Ovarian malignancy risk stratification of the adnexal mass using a multivariate index assay. Gynecol Oncol 128:252–259
Grenache DG, Heichman KA, Werner TL, Vucetic Z (2015) Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass. Clin Chim Acta 438:358–363
Lokshin AE (2012) The quest for ovarian cancer screening biomarkers: are we on the right road? Int J Gynecol Cancer 22(Suppl 1):S35–S40
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Bottoni, P., Scatena, R. (2015). The Role of CA 125 as Tumor Marker: Biochemical and Clinical Aspects. In: Scatena, R. (eds) Advances in Cancer Biomarkers. Advances in Experimental Medicine and Biology, vol 867. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7215-0_14
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DOI: https://doi.org/10.1007/978-94-017-7215-0_14
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