Clarifying the Roles of Glycoprotein Sequence and Cancer Cell Phenotype on the Immunogenicity of Ovarian Cancer Biomarker CA125

Principal Investigator

Rebecca Whelan, Associate Professor, Chemistry

Issue

High-grade serous ovarian cancer (HGSOC) presents a significant challenge in clinical management, with over 220,000 women in the U.S. living with ovarian cancer and at risk of recurrence. There is an unmet need for innovative molecular tools to improve patient outcomes. Reinventing the detection strategy of validated biomarkers is a promising and underutilized approach. The serum marker CA125 is crucial in managing ovarian cancer, yet its underlying mechanism remains poorly understood. The exact identity and location of the CA125 epitopes, detected in clinical tests, are unknown. This lack of understanding impacts crucial decisions in ovarian cancer care, as the CA125 epitopes are located within the tandem-repeat domain of MUC16, a mucin with 19 similar but non-identical subdomains. Variations in MUC16, due to glycan modifications, mRNA splicing, and proteolytic cleavage, result in different proteoforms, only some of which are detectable by the CA125 assay. This undercounting can lead to serious clinical consequences, such as inappropriate referrals and missed early detection of treatable cancer recurrences. Moreover, racial/ethnic differences in serum CA125 levels, particularly lower levels in Black women compared to white women, are not accounted for in current diagnostic tests, potentially leading to higher false negative rates among Black patients.

Response

To enhance the diagnostic value of CA125 and improve the long-term survival of ovarian cancer patients across all backgrounds, a deeper understanding of CA125 epitopes and their distribution on MUC16 is essential. This project aims to map the CA125 epitopes on MUC16 at the amino acid level and investigate their distribution and detectability across different MUC16 proteoforms. The central hypothesis is that CA125 epitopes are unevenly distributed over the tandem-repeat domains of MUC16, unaffected by glycosylation, and vary in abundance depending on the cell type expressing MUC16.

Project Details

The central hypothesis will be tested through two specific aims:

• Map the locations of OC125 and M11 binding on individual tandem repeats of MUC16
• Characterize the binding of OC125 and M11 to intact MUC16 from diverse sources

Successful completion of this research will identify the CA125 epitopes on MUC16 at the amino acid level, providing an unprecedented understanding of the CA125 test. This will reveal regions of MUC16 that can be more effectively detected with novel affinity reagents or non-affinity-based approaches, such as mass spectrometry. Additionally, this research may explain the racial/ethnic differences in serum CA125 levels, improving diagnostic accuracy and patient outcomes.