Study
PLCO
(Learn more about this study)
Project ID
2011-0157
Initial CDAS Request Approval
Nov 14, 2011
Title
Mucins, anti-mucin antibodies and immune complexes as risk and early detection biomarkers for ovarian cancer
Summary
From specimens obtained months or years before ovarian cancer diagnosis, we have accumulated exciting data on early detection and risk biomarkers. In a recently-completed PLCO study, we evaluated 28 biomarkers and found CA125 remains the best biomarker for detecting cases within a year diagnosis. However, 20% of PLCO cases never had CA125 greater than 35 U/ml in the specimen closest to diagnosis or an increase from a prior value. These cases were more likely to score higher in a risk profile built from estimated ovulatory cycles, endometriosis, body mass index, and family history of breast cancer. To explore whether "CA125-occult" cases could be explained by anti-CA125 antibodies bound to CA125 hiding it from its conventional assay, we developed an assay to detect anti-CA125 antibodies, and found them to occur at higher levels in ovarian cancer cases with normal CA125 at diagnosis. Finally, working with specimens from the Nurses Health Study (NHS) taken at least 3 years from diagnosis, we tested a new paradigm for ovarian cancer pathogenesis through events that either increase or decrease immunity to the epithelial cell and cancer marker, MUC1 (related to CA125). The level of anti-MUC1 antibodies tracked with epidemiologic events elevating or lowering risk and a higher level of antibodies correlated with lower ovarian cancer risk in women less than age 64. We now request baseline specimens from women who eventually developed ovarian cancer in PLCO (and matched controls) to determine whether a panel of mucin biomarkers (in combination with the epidemiologic risk profile) could have identified women at either immediate or remote risk for ovarian cancer. The mucin biomarkers will include MUC1 and MUC16 free antigen and anti-MUC1 and anti-MUC16 antibodies and will be measured by an electrochemilumiscent assay. The goal is to improve risk prediction and the early detection of ovarian cancer.
Aims
Using baseline PLCO specimens and epidemiologic data, we will study the epidemiologic correlates of mucin-related biomarkers and the potential of these biomarkers for risk or early detection in combination with an epidemiologic risk profile. We will: 1. Measure HE4, free MUC1 (CA15.3) and MUC16 (CA125) antigens, IgG antibodies against them, and their immune complexes in a set of an estimated 218 cases and 436 controls. 2. Calculate the sensitivity at 95% and 98% specificity and AUC for all cases and cases diagnosed less than 1, 1-2, 2-4, 4-8 and greater than 8 years after the blood collection. 3. Validate key findings from the Nurses Health Study: decline in anti-MUC1 antibodies with aging in controls, younger age at diagnosis associated with lower anti-MUC1 antibody levels, and correlation with ovulatory cycles. 4. Determine if anti-CA125 antibodies may explain false negative CA125 cases. 5. Build a multivariate risk prediction model using the biomarkers and traditional epidemiologic factors, including estimated ovulatory cycles, BMI, history of endometriosis, and others which may correlate with or complement the mucin-related risk or early detection biomarkers.
Collaborators
Su Chun Cheng (Dana Farber Cancer Inst)
Raina Fichorova, MD (Brigham and Women's Hospital)
Daniel W. Cramer (Brigham and Women's Hospital)
Approved Addenda
This project has one or more approved addenda.
- Mucins and HE4 Antigens and Antibody Panel (addendum miRNA's)
