Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene

Abstract

Serum assays based on the CA125 antigen are widely used in the monitoring of patients with ovarian cancer; however very little is known about the molecular nature of the CA125 antigen. We recently cloned a partial cDNA (designated MUC16) that codes for a new mucin that is a strong candidate for being the CA125 antigen. This assignment has now been confirmed by transfecting a partial MUC16 cDNA into 2 CA125-negative cell lines and demonstrating the synthesis of CA125 by 3 different assays. Of the 3 antibodies (OC125, M11 and VK-8) tested on the transfected cells, only the first 2 were strongly positive, indicating the differential expression of the CA125 epitopes in these cells. CA125 is a tumor antigen that forms the basis for a serum assay that is widely used in the monitoring of ovarian and other gynecologic cancers. Subsequent to the development of the first mouse monoclonal antibody (OC125) that detected this antigen in 1981 1 a large number of other anti-CA125 antibodies have been developed. 2 These antibodies have been divided into 3 families (OC125-like, M11-like and Ov197-like) that recognize 3 domains of nonoverlapping epitopes. 2 Most clinical assays use a double determinant assay with 2 antibodies recognizing different epitopes; however a single determinant assay can also be used. 3 CA125 levels are routinely used in gynecologic practice to monitor the clinical status of patients with ovarian cancer. For example, rising CA125 levels during or after treatment often indicate a poor therapeutic response and an unfavorable prognosis. 4 -6 On the other hand, CA125 is of limited use in the initial diagnosis of ovarian cancer because of its elevation in some benign conditions, 4 -6 although possible ways around this limitation are being examined. 7,8 Information on the molecular nature of the CA125 antigen could lead to improved assay methods as well as to an understanding of its biological role in normal and malignant tissues.Most biochemical studies have suggested that the CA125 antigen is a high molecular weight glycoprotein, probably a mucin, although conflicting views have been presented. 9,10 Progress in understanding the molecular nature of CA125 has been hampered by difficulties encountered in attempting to clone this antigen. We have, however, recently isolated a partial cDNA (MUC16) from ovarian cancer cells that is a strong candidate for being the gene coding for the peptide moiety of CA125. 11 The identity of MUC16 as CA125 was based on (i) the isolation of peptides from purified CA125 that were contained in the deduced amino acid sequence of MUC16 and (ii) a precise correlation between MUC16 mRNA expression, determined by Northern blotting and CA125 expression, determined by serological analysis, in a panel of cancer cell lines. We now confirm this identity by demonstrating that CA125-negative cells transfected with MUC16 cDNA synthesize CA125 antigen. We also show the differential expression of CA125 epitopes in the transfected cells. MATERIAL AND METHODS MaterialsAnti-CA125 monoclonal antibod...

MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells

“…NHBE cell cultures, where the predominant gel-forming mucin is MUC5B (Thornton et al, 2000), were thus used for studies of the structure and properties human airway MUC16. As expected from the predicted sequence, which lacks the D-domains required for oligomerization (O'Brien et al, 2001;Yin, Dnistrian & Lloyd, 2002), MUC16 from the cells was monomeric. Secreted MUC16 mucins were very large with the bulk of the population appearing at a position between that of "native" MUC5B and MUC5B subunits upon rate-zonal centrifugation.…”

“…The apparent increase in size seen after reduction of MUC16 may be explained, for instance, by the opening of cysteine loops in the MUC16 repeat domain (O'Brien et al, 2001;Yin, Dnistrian & Lloyd, 2002). No peptides from the extended Nterminal domain of MUC16 could be identified with mass spectroscopy, and it can thus not be determined whether the domain is present in MUC16 from the airways.…”

“…The antigen is now known to be carried by a large mucin-like molecule encoded by the MUC16 gene Yin, Dnistrian & Lloyd, 2002).…”

Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy

“…There are no tumour-specific markers for PC; markers such as serum CA 19-9, DUPAN-2, and CA125 that are being used as potential targets have low specificity (McLaughlin et al, 1999;Rhodes, 1999). For over two decades, the structures of these antigens (CA 19-9, DUPAN2, or CA 125) have been heavily (Yin et al, 2002). At this time, CA19-9 remains the only Food and Drug Administration (FDA)-approved marker to monitor PC.…”

Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125)

“…CA125, a tumor biomarker being used in clinics for the diagnosis of EOC, is actually a mucin (MUC16). 16,17 Despite being a sensitive marker, the utility of CA125/MUC16 is limited owing to its elevation in benign conditions such as, endometriosis, pelvic inflammatory disease and pregnancy. 2,3,5 Another mucin, MUC1 has also been studied in relation to its aberrant expression and pathological functions in ovarian carcinoma.…”