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Title: The identification and characterisation of disease-specific biomarkers in pelvic high grade serous carcinomas
Author: Beirne, James Patrick
ISNI:       0000 0004 6060 9491
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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High grade serous carcinoma (HGSC) is the most common, and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced disease, with a very poor prognosis. Recent pathological evidence suggests HGSC arises from the fimbriae of the distal fallopian tube (FT) via the precursor lesion; serous tubal intra-epithelial carcinoma (STIC). This contradicts the traditional theory that the disease originates in the ovarian surface epithelium (OSE), and carries major translational implications. A unique dataset, incorporating 6 cases of sporadic FIGO IIIC+ HGSC, was curated. For each case, samples of normal OSE, normal FT, STIC, HGSC, and omental metastases were collected. The sample set was interrogated using gene expression profiling and DNA methylation analysis. This was followed by in-depth bioinformatic analysis. Subsequent validation of the profiling data using RqPCR, siRNA screening, and pyrosequencing confirmed the accuracy of the high-throughput arrays. The expression profiling dataset was mined for novel disease-specific biomarkers; a number of which were taken into an ELISA screening strategy within a large external validation sample set. The methylation data-set was mined, in combination with the expression profiling data, for a “proof-of-concept” methylation biomarker. The molecular profile of HGSC shows evidence of mitotic and cell cycle pathways as key drivers of carcinogenesis. Two novel serum protein biomarkers, CHI3L1 and PVRL4, showed promise but failed to complement the diagnostic precision of serum CA125 in a large HGSC validation set (n = 226). A novel methylation biomarker, OSR2, was found to discriminate HGSC from “normal” tissue (p<0.0001). This study provides further evidence that HGSC arises in the FT. Translationally, this strengthens the argument to implement opportunistic risk reducing surgery as a primary prevention strategy. Whilst a novel protein biomarker was not identified a unique DNA methylation biomarker discovery pipeline was established. Further work is required to bring its translational potential to fruition.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available