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

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.

Defining the molecular evolution of extrauterine high grade serous carcinoma.

OBJECTIVE: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC. METHODS: Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model. RESULTS: The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin. CONCLUSION: This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

BRCA1 immunohistochemical staining as a prognostic indicator in uterine serous carcinoma.

OBJECTIVES: The objective of this study was to investigate the relationship between BRCA1 protein expression, as determined by immunohistochemistry, and clinical outcome in uterine serous carcinoma (USC). METHODS: A tissue microarray containing duplicate cores of 73 cases of USC was immunohistochemically stained with mouse anti-BRCA1 (Ab-1) mouse monoclonal (MS110) antibody. The cores were scored in a semiquantitative manner evaluating both the distribution and intensity of nuclear staining. BRCA1 protein expression was correlated with progression-free survival. RESULTS: Seventy-two of 73 cases were assessable, and there was a statistically significant decreased progression-free survival for those cases exhibiting tumor cell nuclei staining of 76% or greater (P = 0.0023). CONCLUSIONS: Our study illustrates that a low level of BRCA1 protein expression is a favorable prognostic indicator in USC, similar to what is observed in high-grade serous ovarian carcinoma. Further studies should focus on the BRCA1 status of USCs at a molecular level and also investigate whether BRCA1 protein expression is associated with response to chemotherapy in USC.