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Understanding the genetic evolution of oral cancer genomes

University of British Columbia

Background: Oral cancer is the most common type of head and neck cancer, with a 5-year survival rate of < 50%. The major problems of oral cancer include the late stage of disease at the time of diagnosis, a lack of effective targeted therapies, and failure in surgical treatment. A better understanding of the genetic evolution of oral cancer will greatly benefit the identification of molecular targets for the prevention and treatment of the disease. I applied whole genome profiling to delineate genes and pathways associated with oral carcinogenesis and to uncover the clonal relationships between samples from the same field. Hypotheses: (i) Genetic alterations critical to oral cancer development will be present in oral premalignant lesions (OPLs), and candidate genes will reside within recurrent regions of alterations in OPLs. (ii) DNA amplification occurs at the premalignant stage of oral cancer development and harbours genes involved in key oncogenic pathways. (iii) The oral cancer field is genetically heterogeneous, and the clonal evolution between biopsies from the field will be revealed by their genetic signatures. Materials/Methods: DNA copy number data from OPLs were generated using tiling-path DNA microarrays. Recurrent regions of alterations on chromosome 3p were identified and associated with clinical information. Copy number data were associated with public expression datasets to identify genes and pathways contributing to oral carcinogenesis. Genetic breakpoints were used to evaluate the clonal expansion of genetically altered cells within a single field. Results: I identified the genetic alterations that are recurrently altered in different individuals, supporting hypothesis 1. Regions of high-level amplification are frequently detected in OPLs, and genes mapped in amplicons are significantly enriched in the FGF signaling network, supporting hypothesis 2. Furthermore, the genetic relatedness among biopsies from an oral cancer field is revealed by comparing their genetic signatures, and the field is found to be genetically heterogeneous, supporting hypothesis 3. Conclusions: Whole genome profiling of OPLs allows the detection of novel genetic changes and fine-maps the genetic breakpoints previously not known. Together, this work highlights the importance of tailored targeted therapy to effectively treat different patients and different subclones of a field.

Text

2010-07-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/26489

Pathology

University of British Columbia

UBCV

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