Patel, Abhilasha (2016) Field cancerisation in colorectal cancer. PhD thesis, University of Warwick.

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Abstract

Colorectal cancer (CRC) continues to cause significant global health burden, despite advances in our understanding of tumour biology, the development of screening programs and increasing public awareness about the disease. Previous studies investigating CRC pathogenesis have been criticised for focussing on the tumour tissue itself. Investigators have proposed that if early biomarkers of disease are to be identified, efforts need to be undertaken in examining pre-neoplastic tissue prior to malignant transformation. Based on the field cancerisation concept, the research hypothesis was that the macroscopically normal mucosa (MNM) around colorectal cancer and polyps is biologically altered. The aims of the study were to determine if the presence of colorectal adenomas at time of cancer diagnosis was predictive of future risk of colonic neoplasia and to characterise the global gene expression profile of MNM adjacent to CRC and adenomas. A retrospective cohort study of CRC patients demonstrated that synchronous adenomas were associated with a higher risk of future adenomas at short term follow up but were not predictive of local recurrence. Thus, other more reliable biological markers of field effect need to be identified. Global gene expression profiles of MNM around cancer, polyps and in control subjects were significantly different when evaluated with micro-array. The differentially expressed genes were involved in immunity, metabolism, epithelial-mesenchymal transition and RNA transcription. CXCL2 and FGF7 were identified as being upregulated in MNM adjacent to CRC suggesting that they could be utilised as markers of field cancerisation in the colon. Further investigation demonstrated that the FGF7-FGFR2 axis was disrupted only at the tumour site with downregulation of some of its downstream targets emphasising the potential role of this signalling axis in CRC formation. Collectively, these findings support the field cancerisation concept in CRC and highlight the importance of signals released by stromal cells in facilitating epithelial growth. These genes may be utilised to develop early biomarkers of disease or could be targeted with pharmacotherapy to modulate future CRC risk.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Library of Congress Subject Headings (LCSH):	Colon (Anatomy) -- Cancer., Rectum -- Cancer.
Official Date:	August 2016
Dates:	Date Event August 2016 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Arasaradnam, Ramesh ; Williams, Nigel ; Tripathi, Gyanendra
Sponsors:	Bowel Disease Research Foundation (BDRF) ; Colorectal Cancer Research Fund (UHCW)
Extent:	291 leaves : illustrations.
Language:	eng

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