Blood glycoprotein biomarkers and ovarian cancer
Research type
Research Study
Full title
Blood glycoprotein biomarkers for early detection or differential diagnosis of ovarian cancer
IRAS ID
258915
Contact name
Usha Menon
Contact email
Sponsor organisation
University College London
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Research Summary
Detection of ovarian cancer at an early stage greatly improves the survival rate. Most ovarian cancer cases are diagnosed at advanced stages when <30% will survive for 5 years. Diagnosis at early stages improves the 5-year survival to ~90%. Therefore, implementation of an effective screening test is expected to improve ovarian cancer outcomes through early diagnosis. A test or biomarkers with sufficient sensitivity for early ovarian cancer screening is crucial. Identification of new biomarkers for early ovarian cancer would be a game-changer in the quest to reduce mortality due to ovarian cancer.This project focuses on finding blood proteins that can distinguish women with high grade serous ovarian cancer from benign ovarian conditions and healthy (no cancer) individuals. High grade serous ovarian cancer is the most common subtype of ovarian cancer with poor outcome. For this project, serum samples previously collected from volunteers during the course of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial and the Risk Prediction and Early Detection of Ovarian Cancer (UKOPS) study who were later diagnosed with ovarian cancer will be used. Controls (no record of cancer diagnosis) as well as women with benign ovarian pathology will also be selected for comparison. In collaboration with Associate Professor Hill, proteins in the blood samples will be analysed in a nested case-control study using our collaborator’s proven method for blood protein biomarker discovery.
Summary of Results
Detection of ovarian cancer at an early stage greatly improves the survival rate. Most ovarian cancer cases are diagnosed at advanced stages when <30% will survive for 5 years. Diagnosis at early stages improves the 5-year survival to ~90%. Therefore, a test or biomarkers with sufficient sensitivity for early ovarian cancer screening is crucial. This project focused on finding blood-based (serum) proteins that can distinguish women with high-grade serous ovarian cancer from benign ovarian conditions and healthy (no cancer) individuals. High-grade serous ovarian cancer is the most common subtype of ovarian cancer with poor outcome.For this project, a subset of serum samples previously collected from volunteers during the course of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial and the Risk Prediction and Early Detection of Ovarian Cancer (UKOPS) study who were later diagnosed with ovarian cancer were used. Controls (no record of cancer diagnosis) as well as women with benign ovarian pathology were also selected for comparison. In brief, for the investigation of the early detection biomarkers, serum samples previously collected from the single sample arms of the UKCTOCS trial were selected. These included a subset of those collected up to 18 months before diagnosis of (1) high-grade serous ovarian cancer, (2) benign serous ovarian disease/pathology and (3) age-matched controls with no known cancer history at the time of sample selection. Ten subjects in each category were selected. For the investigation of the differential diagnosis biomarkers, serum samples collected prior to treatment during the course of the UKOPS study were selected. These included 30 subjects with (1) high-grade serous ovarian carcinoma, (2) benign serous ovarian pathology and (3) age-matched controls with no known history of cancer at the time of sample selection. As before, 10 subjects in each category were selected.
In collaboration with Associate Professor Hill, proteins in the serum samples were analysed in a nested case-control study using our collaborator’s proven method for blood protein biomarker discovery. This project used known changes in the blood protein sugar side chains (glycans) to find potential biomarkers for high-grade serous ovarian cancer. Cancers are known to carry changes in the machinery that add the glycans to blood proteins (Pinho & Reis 2015). Prof Hill’s lab has previously published a number of papers in oesophageal adenocarcinoma describing in detail their established methodology that will also be applied in this study (Loo et al. 2009, Choi et al. 2011, Shah et al. 2015, 2018). Based on the well-characterised role of glycosylation changes during cancer development our collaborator’s novel method utilises a lectin array to detect changes in glycosylation type. Briefly, the pipeline consisted of lectin-coupled magnetic beads for isolation of glycosylated proteins based on their glycosylation structures. In the discovery phase, proteins will be identified by liquid chromatography tandem mass spectrometry (LC-MS/MS) using data dependent acquisition on an orbitrap mass spectrometer.
During the laboratory analysis the case/control status was unknown to the collaborator. Upon completion of all the experimental work the core UCL team provided additional clinical and epidemiological information (such as age at diagnosis, age at sample collection, BMI, hormone-replacement therapy use, reproductive history, smoking history, alcohol consumption) so that statistical analysis could proceed using all parameters. Analysis of the samples unfortunately coincided with the Covid19 pandemic and due to this there were some unforeseen delays in the timelines for completion. Despite these delays the project continued and applying unique biomarker workflow to serum samples the data was analysed to generate a list of candidate biomarkers that would inform the future verification phase(s). Our collaborator identified 108 new blood proteins that are different in the blood of ovarian cancer patients compared to benign and healthy patients. These proteins have not been previously reported in relation to ovarian cancer diagnosis, and therefore represent new biomarker candidates that could potentially help in ovarian cancer screening and diagnosis using a blood test. These candidates were also measured in an independent set of 100 ovarian cancer patient samples (validation set) that our collaborator received from another Institution (Mater Ovarian Cancer Research Collaborative biobank, Brisbane, Australia), to determine their diagnostic accuracy and whether they can detect early-stage ovarian cancer. Results from this second phase (validation) confirmed some of the data/biomarkers identified from the previous phase using UKCTOCS/UKOPS sets.
REC name
East Midlands - Derby Research Ethics Committee
REC reference
19/EM/0089
Date of REC Opinion
13 Mar 2019
REC opinion
Favourable Opinion