The CA125 gene has been cloned and multiple repeat sequences as well as
the carboxy terminus have been identified. The CA125 molecule comprises
three major domains: an extracellular amino terminal domain (Domain 1); a
large multiple repeat domain (Domain 2); and a carboxy terminal domain
(Domain 3) which includes a transmembrane anchor with a short cytoplasmic
domain. The amino terminal domain is assembled by combining five genomic
exons, four very short amino terminal sequences and one extraordinarily
large exon. This domain is dominated by its capacity for O-glycosylation
and its resultant richness in serine and threonine residues.
Additionally, an amino terminal extension is present, which comprises
four genomic exons. The amino acid composition of the amino terminal
extension was found to be consistent with the amino acid composition of
the amino terminal domain. The molecular structure is dominated by a
repeat domain comprising 156 amino acid repeat units, which encompass the
epitope binding sites. More than 60 repeat units have been identified,
sequenced, and contiguously placed in the CA125 domain structure. The
repeat units encompass an interactive disulfide bridged C-enclosure and
the site of OC125 and M11 binding. The repeat sequences demonstrated
70-85% homology to each other. Expression of the repeats was demonstrated
in E. coli. The CA125 molecule is anchored at its carboxy terminal
through a transmembrane domain and a short cytoplasmic tail. The carboxy
terminal also contains a proteolytic cleavage site approximately 50 amino
acids upstream from the transmembrane domain, which allows for
proteolytic cleavage and release of the CA125 molecule. Any one of the
repeat domains has the potential for use as a new gold standard for
detecting and monitoring the presence of the CA125 antigen. Further, the
repeat domains or other domains, especially the c-terminal to the repeat
domain also provide a basis for the development of a vaccine, which would
be useful for the treatment of ovarian cancer and other carcinomas where
CA125 is elevated.