UBC Theses and Dissertations
Genetic alterations and lineage specificity in lung cancer Lockwood, William W.
Background: Lung cancer is the world's leading cause of cancer mortality. The main factors contributing to this are the late stage of disease at the time of diagnosis and a lack of effective chemotherapeutic strategies. A better understanding of the molecular origins and basic biology of lung cancer will lead to the development of early detection techniques and novel therapies to address these issues. I applied an integrative genomics approach utilizing high-resolution whole genome profiling technologies to uncover causal gene disruption in lung cancer and identify candidates associated with the development of specific lung cancer subtypes. Hypotheses: (i) Genes key to lung tumorigenesis will be identified in recurrently altered genomic regions. (ii) Lung cancer subtypes require distinct genetic alterations for neoplastic development. Materials/ Methods: DNA copy number data from lung cancer specimens were integrated with expression data to identify genes contributing to tumorigenesis. Subsequently, this approach was applied to compare lung cancer subtypes to discover genes and pathways specifically disrupted in each. Quantitative RT-PCR and immunohistochemistry were performed to validate results from microarray experiments and cell models were utilized to confirm the functional significance of identified genes. Results: I identified novel gene candidates frequently deregulated in lung cancer which contribute to tumorigenesis, supporting the first hypothesis. In addition, the comparison of lung cancer subtypes identified subtype-specific genetic events and delineated genes and pathways important in their differential development, supporting the second hypothesis. Significantly, I discovered a novel squamous cell lineage specific oncogene, BRF2, which affects polymerase III transcribed genes. Conclusions: Integrative genomic analysis is an effective means for identifying key gene disruptions in lung cancer. Furthermore, these findings suggest that lung cancer subtypes require distinct genetic alterations for tumorigenesis, uncovering the specific targets disrupted by these alterations for the first time. Most importantly, activation of BRF2 represents a novel mechanism of tumorigenesis through the increase of polymerase III mediated transcription and the targeted activation of this gene in SqCC suggests that it may be an excellent candidate for new treatment strategies tailored to this subtype. Together, this work highlights the need for tailoring therapies to the specific cancer subtypes.
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