From Wikipedia, the free encyclopedia
Jump to: navigation, search

This is a work in progress for the CA-125 page. Any feedback would be appreciated. --K. Beabout (talk) 22:54, 5 April 2012 (UTC)

Mucin 16, cell surface associated
The Structure of MUC16 2.jpeg
Symbols MUC16 ; CA125
External IDs OMIM606154 HomoloGene133291 GeneCards: MUC16 Gene
Species Human Mouse
Entrez 94025 73732
Ensembl ENSG00000181143 ENSMUSG00000032134
UniProt Q8WXI7 Q9D1H1
RefSeq (mRNA) NM_024690 n/a
RefSeq (protein) NP_078966 n/a
Location (UCSC) Chr 19:
8.85 – 8.98 Mb
Chr 9:
18.3 – 18.32 Mb
PubMed search [1] [2]

CA-125 (cancer antigen 125 or carbohydrate antigen 125) also known as mucin 16 or MUC16 is a protein that in humans is encoded by the MUC16 gene.[1][2] MUC16 is a member of the mucin family glycoproteins.[3] CA-125 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers,[4] or other benign conditions.


Mucin 16 is a membrane associated mucin that possesses a single transmembrane domain.[5] A unique property of MUC16 is its large size. MUC16 is more than twice as long as MUC1 and MUC4 and contains about 22,000 amino acids, making it the largest membrane associated mucin.[6]

MUC16 is composed of three different domains:[7]

The N-terminal and tandem repeat domains are both entirely extracellular and highly O-glycosylated. All mucins contain a tandem repeat domain that has repeating sequences high in serine, threonine and proline.[8] The C-terminal domain contains multiple extracellular SEA (sea urchin sperm protein, enterokinase, and agrin) modules,[9] a transmembrane domain, and a cytoplasmic tail.[7] The extracellular region of MUC16 can be released from the cell surface by undergoing proteolytic cleavage.[10] MUC16 is thought to be cleaved at a site in the SEA modules.[11]


MUC16 is a component of the ocular surface (including the cornea and conjunctiva), the respiratory tract and the female reproductive tract epithelia. Since MUC16 is highly glycosylated it creates a hydrophilic environment that acts as a lubricating barrier against foreign particles and infectious agents on the apical membrane of epithelial cells.[12] Also, the cytoplasmic tail of MUC16 has been shown to interact with cytoskeleton by binding members of the ERM protein family.[13] The expression of mucin 16 has been shown to be altered in dry eye, cystic fibrosis, and several types of cancers.[14]

As a biomarker[edit]

CA-125 is the most frequently used biomarker for ovarian cancer detection.[15] Around 90% of women with advanced ovarian cancer have elevated levels of CA-125 in their blood serum, making CA-125 a useful tool for detecting ovarian cancer after the onset of symptoms.[16] Monitoring CA-125 blood serum levels is also useful for determining how ovarian cancer is responding to treatment (with the duration of disease-free survival correlating with the rate of fall of CA-125)[17] and for predicting a patient’s prognosis after treatment.[18] This is because the persistence of high levels of CA-125 during therapy is associated with poor survival rates in patients.[18] Also, an increase in CA-125 levels within individuals in a remission is a strong predictor of the recurrence of ovarian cancer.[19] Indeed, a rising CA-125 level may precede clinical evidence of disease relapse by an interval of 3 to 6 months.

Prognosis relates to both the initial and post-treatment CA-125 values. A preoperative value >65 U/mL suggests a poor prognosis. Persistent elevations following chemotherapy indicate a poor prognosis. The half-life of CA-125 after chemotherapy correlates with prognosis (patients with CA-125 half-life <20 days show improved survival). Time-to-normalization (rate of fall of CA-125) affects prognosis with more rapid normalization within 3 cycles of chemotherapy correlating with improved survival.[20]

In April 2011 the UK's National Institute for Health and Clinical Excellence (NICE) recommended that women with symptoms that could be caused by ovarian cancer should be offered a CA-125 blood test.[21] The aim of this guideline is to help diagnose the disease at an earlier stage, when treatment is more likely to be successful. Women with higher levels of the marker in their blood would then be offered an ultrasound scan to determine whether they need further tests.

In one case, elevated serum levels of CA-125 were observed in a male patient with IgE myeloma, however more cases are needed to determine the clinical significance of CA-125 in myeloma.[22]

Early detection of ovarian cancer[edit]

The potential role of CA-125 for the early detection of ovarian cancer is controversial and has not yet been adopted for widespread screening efforts in asymptomatic women.[23][24] The major issues with using the CA-125 biomarker are its lack of sensitivity, particularly for detecting early stages of ovarian cancer, and its lack of specificity, especially in premenopausal women.[25] These limitations mean that CA-125 testing often gives false positives for ovarian cancer and puts patients through unnecessary further screening (sometimes including surgery) and anxiety.[26] Also, these limitations mean that many women with early stage ovarian cancer will receive a false negative from CA-125 testing and not get further treatment for their condition.[27]

Specificity and sensitivity[edit]

CA-125 has limited specificity for ovarian cancer because elevated CA-125 levels can be found in individuals without ovarian cancer. For example, while CA-125 is best known as a marker for ovarian cancer,[28] it may also be elevated in other cancers, including endometrial cancer, fallopian tube cancer, lung cancer, breast cancer and gastrointestinal cancer.[29] CA-125 may also be elevated in a number of relatively benign conditions, such as endometriosis,[30] several diseases of the ovary, menstruation[25] and pregnancy.[31] It also tends to be elevated in the presence of any inflammatory condition in the abdominal area, both cancerous and benign,[32] as well as in cirrhosis and diabetes mellitus. [33] Thus, CA-125 testing is not perfectly specific for ovarian cancer and often results in false positives.[25]

The specificity of CA-125 is particularly low in premenopausal women because many benign conditions that cause fluctuations in CA-125 levels, such as menstruation, pregnancy, and pelvic inflammatory disease, are seen in this population.[24]

CA-125 testing is also not perfectly sensitive for detecting ovarian cancer because not every patient with cancer will have elevated levels of CA-125 in their blood.[34] For example, 79% of all ovarian cancers are positive for CA-125, whereas the remainder do not express this antigen at all.[35] Also, only about 50% of patients with early stage ovarian cancer have elevated CA-125 levels, meaning that CA-125 has particularly poor sensitivity for ovarian cancer before the onset of symptoms.[36][25] Poor sensitivity means that the use of CA-125 to detect ovarian cancer (especially in early stages of disease) can frequently lead to false negatives. Patients that receive false negatives are unlikely to seek further treatment for their disease.

Ranges in ovarian cancer[edit]

While this test is not generally regarded as useful for large scale screening by the medical community, a high value may be an indication that the woman should receive further diagnostic screening or treatment. Normal values range from 0 to 35 (U/mL).[25] Elevated levels in post-menopausal women are usually an indication that further screening is necessary. In pre-menopausal women, the test is less reliable as values are often elevated due to a number of non-cancerous causes, and a value above 35 is not necessarily a cause for concern.[24]

In a patient who is clinically selected for testing due to the presence of an adnexal/pelvic mass, CA-125 has great utility to differentiate benign from malignant processes. In a post-menopausal woman with a palpable adnexal mass and CA-125 level greater than 65 U/mL, the positive predictive value is >95% for ovarian malignancy. In patients who are not as carefully selected clinically, the utility of this test decreases, thus highlighting the need for careful clinical scrutiny.

Role in cancer[edit]

Tumor metastasis initiated by interactions between MUC16 and mesothelin.

MUC16 has been shown to play a role in advancing tumorigenesis and tumor proliferation by several different mechanisms.

Immune system evasion[edit]

One way that MUC16 helps the growth of tumors is by suppressing the response of natural killer cells, which protects the cancer cells from the immune response.[37] Further evidence that MUC16 can protect tumor cells from the immune system is the discovery that the heavily glycosylated tandem repeat domain of MUC16 can bind to galectin-1 (an immunosuppressive protein).[38]

Metastatic invasion[edit]

MUC16 is also thought to participate in cell-to-cell interactions that allow for the metastasis of tumor cells. This is supported by evidence showing that MUC16 binds selectively to mesothelin, a glycoprotein normally expressed by the mesothelial cells of the peritoneum (the lining of the abdominal cavity).[39] MUC16 and mesothelin interactions are thought to provide the first step in tumor cell invasion of the peritoneum.[40]

Mesothelin has also been found to be expressed in several types of cancers including mesothelioma, ovarian cancer and squamous cell carcinoma.[41] Since mesothelin is also expressed by tumor cells, MUC16 and mesothelial interactions may aid in the gathering of other tumor cells to the location of a metastasis, thus increasing the size of the metastasis.[40]

Induced motility[edit]

Evidence suggests that expression of the cytoplasmic tail of MUC16 enables tumor cells to grow, promotes cell motility and may facilitate invasion. This appears to be due to the ability of the C-terminal domain of MUC16 to facilitate signaling that leads to a decrease in the expression of E-cadherin and increase the expression of N-cadherin and vimentin, which are expression patterns consistent with epithelial-mesenchymal transition.[42]

Chemotherapy resistance[edit]

MUC16 might also play a role in reducing the sensitivity of cancer cells to drug therapy. Overexpression of MUC16 has been shown to protect cells from the effects of genotoxic drugs, such as cisplatin.[43]


CA-125 was initially detected using the murine monoclonal antibody designated OC125. Drs. Robert Bast, Robert Knapp and their research team first isolated this monoclonal antibody in 1981.[44] The protein was named “cancer antigen 125” because OC125 was the 125th antibody produced against the ovarian cancer cell line that was being studied.[45]


  1. ^ Yin BW, Lloyd KO (2001). "Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16". J. Biol. Chem. 276 (29): 27371–5. doi:10.1074/jbc.M103554200. PMID 11369781.  Unknown parameter |month= ignored (help)
  2. ^ Yin BW, Dnistrian A, Lloyd KO (2002). "Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene". Int. J. Cancer. 98 (5): 737–40. doi:10.1002/ijc.10250. PMID 11920644.  Unknown parameter |month= ignored (help)
  3. ^ Duraisamy S, Ramasamy S, Kharbanda S, Kufe D (2006). "Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16". Gene. 373: 28–34. doi:10.1016/j.gene.2005.12.021. PMID 16500040.  Unknown parameter |month= ignored (help)
  4. ^ Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB (1998). "CA 125: the past and the future". Int. J. Biol. Markers. 13 (4): 179–87. PMID 10228898. 
  5. ^ Gipson IK (2007). "The ocular surface: the challenge to enable and protect vision: the Friedenwald lecture". Invest. Ophthalmol. Vis. Sci. 48 (10): 4390; 4391–8. doi:10.1167/iovs.07-0770. PMC 2886589Freely accessible. PMID 17898256.  Unknown parameter |month= ignored (help)
  6. ^ Gniewek P, Kolinski A (2012). "Coarse-Grained Modeling of Mucus Barrier Properties". Biophys. J. 102 (2): 195–200. doi:10.1016/j.bpj.2011.11.4010. ISSN 0006-3495. PMID 22339855.  Unknown parameter |month= ignored (help)
  7. ^ a b O'Brien TJ, Beard JB, Underwood LJ, Dennis RA, Santin AD, York L (2001). "The CA 125 gene: an extracellular superstructure dominated by repeat sequences". Tumour Biol. 22 (6): 348–66. doi:10.1159/000050638. PMID 11786729.  Unknown parameter |month= ignored (help)
  8. ^ Hollingsworth MA, Swanson BJ (2004). "Mucins in cancer: protection and control of the cell surface". Nat. Rev. Cancer. 4 (1): 45–60. doi:10.1038/nrc1251. PMID 14681689.  Unknown parameter |month= ignored (help)
  9. ^ Kufe DW (2009). "Mucins in cancer: function, prognosis and therapy". Nat. Rev. Cancer. 9 (12): 874–85. doi:10.1038/nrc2761. PMC 2951677Freely accessible. PMID 19935676.  Unknown parameter |month= ignored (help)
  10. ^ Goodell CA, Belisle JA, Gubbels JA, Migneault M, Rancourt C, Connor J, Kunnimalaiyaan M, Kravitz R, Tucker W, Zwick M, Patankar MS (2009). "Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies". J Ovarian Res. 2 (1): 8. doi:10.1186/1757-2215-2-8. PMC 2708168Freely accessible. PMID 19538730. 
  11. ^ Palmai-Pallag T, Khodabukus N, Kinarsky L, Leir SH, Sherman S, Hollingsworth MA, Harris A (2005). "The role of the SEA (sea urchin sperm protein, enterokinase and agrin) module in cleavage of membrane-tethered mucins". FEBS J. 272 (11): 2901–11. doi:10.1111/j.1742-4658.2005.04711.x. PMID 15943821.  Unknown parameter |month= ignored (help)
  12. ^ Perez BH, Gipson IK (2008). "Focus on Molecules: human mucin MUC16". Exp. Eye Res. 87 (5): 400–1. doi:10.1016/j.exer.2007.12.008. PMC 2586928Freely accessible. PMID 18289532.  Unknown parameter |month= ignored (help)
  13. ^ Blalock TD, Spurr-Michaud SJ, Tisdale AS, Heimer SR, Gilmore MS, Ramesh V, Gipson IK (2007). "Functions of MUC16 in corneal epithelial cells". Invest. Ophthalmol. Vis. Sci. 48 (10): 4509–18. doi:10.1167/iovs.07-0430. PMID 17898272.  Unknown parameter |month= ignored (help)
  14. ^ Bafna S, Kaur S, Batra SK (2010). "Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells". Oncogene. 29 (20): 2893–904. doi:10.1038/onc.2010.87. PMC 2879972Freely accessible. PMID 20348949.  Unknown parameter |month= ignored (help)
  15. ^ Suh KS, Park SW, Castro A, Patel H, Blake P, Liang M, Goy A (2010). "Ovarian cancer biomarkers for molecular biosensors and translational medicine". Expert Rev. Mol. Diagn. 10 (8): 1069–83. doi:10.1586/erm.10.87. PMID 21080822.  Unknown parameter |month= ignored (help)
  16. ^ Gupta D, Lis CG (2010). "Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature". Nutr J. 9: 69. doi:10.1186/1475-2891-9-69. PMC 3019132Freely accessible. PMID 21176210. 
  17. ^ Bast RC, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR, Knapp RC (1983). "A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer". N. Engl. J. Med. 309 (15): 883–7. doi:10.1056/NEJM198310133091503. PMID 6310399.  Unknown parameter |month= ignored (help)
  18. ^ a b Göcze P, Vahrson H (1993). "[Ovarian carcinoma antigen (CA 125) and ovarian cancer (clinical follow-up and prognostic studies)]". Orv Hetil (in Hungarian). 134 (17): 915–8. PMID 8479736.  Unknown parameter |month= ignored (help)
  19. ^ Santillan A, Garg R, Zahurak ML, Gardner GJ, Giuntoli RL, Armstrong DK, Bristow RE (2005). "Risk of epithelial ovarian cancer recurrence in patients with rising serum CA-125 levels within the normal range". J. Clin. Oncol. 23 (36): 9338–43. doi:10.1200/JCO.2005.02.2582. PMID 16361633.  Unknown parameter |month= ignored (help)
  20. ^ Mais DD, Leonard GR (2009). Quick Compendium Companion for Clinical Pathology (2nd ed.). Chicago: American Society for Clinical Pathology. p. 352. ISBN 0-89189-579-5. 
  21. ^ "Women should be offered a blood test for ovarian cancer". NICE guidance. United Kingdom National Institute for Health and Clinical Excellence. 2011-04-27. Retrieved 2012-04-14. 
  22. ^ Wang ML, Huang Q, Yang T (2009). "IgE myeloma with elevated level of serum CA125". J Zhejiang Univ Sci B. 10 (7): 559–562. doi:10.1631/jzus.B0820399. PMID 19585675.  Unknown parameter |month= ignored (help)
  23. ^ Baron, JA (2012). "Screening for cancer with molecular markers: progress comes with potential problems". Nat. Rev. Cancer. 12 (5): 1379–80. doi:10.1038/nrc3260. PMID 22495319.  Unknown parameter |month= ignored (help)
  24. ^ a b c Fritsche HA, Bast RC (1998). "CA 125 in ovarian cancer: advances and controversy". Clin. Chem. 44 (7): 1379–80. PMID 9665412.  Unknown parameter |month= ignored (help)
  25. ^ a b c d e Nossov V, Amneus M, Su F, Lang J, Janco JM, Reddy ST, Farias-Eisner R (2008). "The early detection of ovarian cancer: from traditional methods to proteomics. Can we really do better than serum CA-125?". Am. J. Obstet. Gynecol. 199 (3): 215–23. doi:10.1016/j.ajog.2008.04.009. PMID 18468571.  Unknown parameter |month= ignored (help)
  26. ^ Santillan A, Garg R, Zahurak ML, Gardner GJ, Giuntoli RL, Armstrong DK, Bristow RE (2005). "Risk of epithelial ovarian cancer recurrence in patients with rising serum CA-125 levels within the normal range". J. Clin. Oncol. 23 (36): 9338–43. doi:10.1200/JCO.2005.02.2582. PMID 16361633.  Unknown parameter |month= ignored (help)
  27. ^ E L Moss, J Hollingworth, T M Reynolds (2004). "The role of CA125 in clinical practice". J. Clin. Pathol. 58 (3): 308–312. doi:10.1136/jcp.2004.018077. PMID 15735166.  Unknown parameter |month= ignored (help)
  28. ^ Osman N, O'Leary N, Mulcahy E, Barrett N, Wallis F, Hickey K, Gupta R (2008). "Correlation of serum CA125 with stage, grade and survival of patients with epithelial ovarian cancer at a single centre". Ir Med J. 101 (8): 245–7. PMID 18990955.  Unknown parameter |month= ignored (help)
  29. ^ Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB (1998). "CA 125: the past and the future". Int. J. Biol. Markers. 13 (4): 179–87. PMID 10228898. 
  30. ^ Bagan P, Berna P, Assouad J, Hupertan V, Le Pimpec Barthes F, Riquet M (2008). "Value of cancer antigen 125 for diagnosis of pleural endometriosis in females with recurrent pneumothorax". Eur. Respir. J. 31 (1): 140–2. doi:10.1183/09031936.00094206. PMID 17804443.  Unknown parameter |month= ignored (help)
  31. ^ Sarandakou A, Protonotariou E, Rizos D (2007). "Tumor markers in biological fluids associated with pregnancy". Crit Rev Clin Lab Sci. 44 (2): 151–78. doi:10.1080/10408360601003143. PMID 17364691. 
  32. ^ Asher V, Hammond R, Duncan TJ (2010). "Pelvic mass associated with raised CA 125 for benign condition: a case report". World J Surg Oncol. 8: 28. doi:10.1186/1477-7819-8-28. PMC 2861664Freely accessible. PMID 20398372. 
  33. ^ Faulkner D, Meldrum C (2012). "Tumour markers". Australian Prescriber. 35 (4): 125–8. 
  34. ^ Ferrini R (1997). "Screening asymptomatic women for ovarian cancer: American College of Preventive Medicine practice policy" (PDF). Am J Prev Med. 13 (6): 444–6. PMID 9415790. 
  35. ^ Rosen DG, Wang L, Atkinson JN, Yu Y, Lu KH, Diamandis EP, Hellstrom I, Mok SC, Liu J, Bast RC (2005). "Potential markers that complement expression of CA125 in epithelial ovarian cancer". Gynecol. Oncol. 99 (2): 267–77. doi:10.1016/j.ygyno.2005.06.040. PMID 16061277.  Unknown parameter |month= ignored (help)
  36. ^ Sasaroli D, Coukos G, Scholler N (2009). "Beyond CA125: the coming of age of ovarian cancer biomarkers. Are we there yet?". Biomark Med. 3 (3): 275–288. doi:10.2217/bmm.09.21. PMC 2726755Freely accessible. PMID 19684876.  Unknown parameter |month= ignored (help)
  37. ^ Patankar MS, Jing Y, Morrison JC, Belisle JA, Lattanzio FA, Deng Y, Wong NK, Morris HR, Dell A, Clark GF (2005). "Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125". Gynecol. Oncol. 99 (3): 704–13. doi:10.1016/j.ygyno.2005.07.030. PMID 16126266.  Unknown parameter |month= ignored (help)
  38. ^ 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 (Pt 7): 1305–18. PMID 12615972.  Unknown parameter |month= ignored (help)
  39. ^ Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A (2004). "Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion". J. Biol. Chem. 279 (10): 9190–8. doi:10.1074/jbc.M312372200. PMID 14676194.  Unknown parameter |month= ignored (help)
  40. ^ a b Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I, Patankar MS (2006). "Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors". Mol. Cancer. 5 (1): 50. doi:10.1186/1476-4598-5-50. PMC 1635730Freely accessible. PMID 17067392. 
  41. ^ Chang K, Pastan I (1996). "Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers". Proc. Natl. Acad. Sci. U.S.A. 93 (1): 136–40. doi:10.1073/pnas.93.1.136. PMC 40193Freely accessible. PMID 8552591.  Unknown parameter |month= ignored (help)
  42. ^ Thériault C, Pinard M, Comamala M, Migneault M, Beaudin J, Matte I, Boivin M, Piché A, Rancourt C (2011). "MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis". Gynecol. Oncol. 121 (3): 434–43. doi:10.1016/j.ygyno.2011.02.020. PMID 21421261.  Unknown parameter |month= ignored (help)
  43. ^ Boivin M, Lane D, Piché A, Rancourt C (2009). "CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis". Gynecol. Oncol. 115 (3): 407–13. doi:10.1016/j.ygyno.2009.08.007. PMID 19747716.  Unknown parameter |month= ignored (help)
  44. ^ Bast RC, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC (1981). "Reactivity of a monoclonal antibody with human ovarian carcinoma". J. Clin. Invest. 68 (5): 1331–7. doi:10.1172/JCI110380. PMC 370929Freely accessible. PMID 7028788.  Unknown parameter |month= ignored (help)
  45. ^ Schmidt C (2011). "CA-125: a biomarker put to the test. Journal of the National Cancer Institute". J. Natl. Cancer Inst. 103 (17): 1290–1. doi:10.1093/jnci/djr344. PMID 21852262.  Unknown parameter |month= ignored (help)

Further reading[edit]

External links[edit]

Category:Tumor markers