A bespoke target selection tool to guide biomarker discovery in tubo-ovarian cancer

James P Beirne; Alan Gilmore; Caitríona E McInerney; Aideen Roddy; W Glenn McCluggage; Ian J G Harley; M Abdullah Alvi; Kevin M Prise; Darragh G McArt; Paul B Mullan

doi:10.1016/j.csbj.2022.06.016

A bespoke target selection tool to guide biomarker discovery in tubo-ovarian cancer

Comput Struct Biotechnol J. 2022 Jun 17:20:3359-3371. doi: 10.1016/j.csbj.2022.06.016. eCollection 2022.

Authors

James P Beirne^{1

2

3}, Alan Gilmore², Caitríona E McInerney², Aideen Roddy², W Glenn McCluggage^{2

4

3}, Ian J G Harley^{2

3}, M Abdullah Alvi⁵, Kevin M Prise¹, Darragh G McArt², Paul B Mullan²

Affiliations

¹ Department of Gynaecological Oncology, Trinity St. James Cancer Institute, Dublin, Ireland.
² Patrick G. Johnson Centre for Cancer Research, Queen's University, Belfast, Northern Ireland.
³ Northern Ireland Gynaecological Cancer Centre, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland.
⁴ Department of Histopathology, Royal Group of Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland.
⁵ Precision Medicine Centre of Excellence, Queen's University, Belfast, Northern Ireland.

Abstract

Introduction: Cancers presenting at advanced stages inherently have poor prognosis. High grade serous carcinoma (HGSC) is the most common and aggressive form of tubo-ovarian cancer. Clinical tests to accurately diagnose and monitor this condition are lacking. Hence, development of disease-specific tests are urgently required.

Methods: The molecular profile of HGSC during disease progression was investigated in a unique patient cohort. A bespoke data browser was developed to analyse gene expression and DNA methylation datasets for biomarker discovery. The Ovarian Cancer Data Browser (OCDB) is built in C# with a.NET framework using an integrated development environment of Microsoft Visual Studio and fast access files (.faf). The graphical user interface is easy to navigate between four analytical modes (gene expression; methylation; combined gene expression and methylation data; methylation clusters), with a rapid query response time. A user should first define a disease progression trend for prioritising results. Single or multiomics data are then mined to identify probes, genes and methylation clusters that exhibit the desired trend. A unique scoring system based on the percentage change in expression/methylation between disease stages is used. Results are filtered and ranked using weighting and penalties.

Results: The OCDB's utility for biomarker discovery is demonstrated with the identified target OSR2. Trends in OSR2 repression and hypermethylation with HGSC disease progression were confirmed in the browser samples and an independent cohort using bioassays. The OSR2 methylation biomarker could discriminate HGSC with high specificity (95%) and sensitivity (93.18%).

Conclusions: The OCDB has been refined and validated to be an integral part of a unique biomarker discovery pipeline. It may also be used independently to aid identification of novel targets. It carries the potential to identify further biomarker assays that can reduce type I and II errors within clinical diagnostics.

Keywords: Biomarkers; Carcinoogenesis; High grade serous carcinoma; Integromics; Interactive data browser; Methylation profiling; Molecular profiling; Tubo-ovarian cancer.