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The molecular characterization of the progression of oral squamous cell carcinoma

University of British Columbia

Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck cancer and has a relatively low five year survival rate of ~50%. One of the reasons for this high mortality rate is that patients are generally diagnosed at late stages. OSCC develops through a typical histological progression and although lesions in the oral cavity are visible at the premalignant stage, it is not possible to predict which lesions will progress based on histology alone. In-depth analysis of genome-wide molecular alterations may identify novel genes or pathways that can be used as biomarkers or therapeutic targets in order to improve survival rates of this disease. In this thesis, I perform DNA methylation, gene expression and miRNA profiling on a panel of patient tissue samples, each with a paired adjacent normal, dysplasia and either a carcinoma in situ or squamous cell carcinoma, taken from a single contiguous disease field within a patient’s oral cavity. My hypotheses are that the epigenetic landscape of OSCC becomes progressively more deregulated throughout the different histological stages and that the most frequently altered molecular events identified at the dysplasia stage may be crucial for premalignant disease development and progression. A high level of deregulation in both methylation and miRNA patterns as the disease progresses is observed, and a number of highly frequent molecular events are identified. Several of these molecular events are then functionally validated to assess the ability to contribute to tumorigenesis in oral premalignant lesions. Taken together, this thesis provides one of the most comprehensive epigenetic analyses of paired normal, dysplasia and CIS/SCC biopsies with regards to DNA methylation and miRNA profiling. In addition to providing a deeper insight into the molecular mechanisms at play within the premalignant lesions, we also validate the ability of these mechanisms to directly contribute to tumorigenesis.

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2016-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59026

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/