UBC Theses and Dissertations
Global approaches to identifying aberrations in early staged disease in cancers affecting women Shadeo, Ashleen
INTRODUCTION: Breast and cervical cancer are the most common cancers in women worldwide. Widely implemented screening programs have allowed for the detection of precancerous lesions in the breast and cervix and have provided a valuable opportunity to study the earliest events in disease development with the goal of distinguishing cases that are likely to progress from those that are self limited or would spontaneously regress. OBJECTIVE: The overall objective of this thesis is to identify genes in biological pathways or networks altered in pre cancerous lesions of the breast and cervix using global analysis tools. HYPOTHESIS: I hypothesize that global transcriptome and high resolution genome analysis will identify altered genes that are shared in pre cancer lesions of both the cervix and breast. METHODS: A comprehensive Serial Analysis of Gene Expression method was used for the unbiased analysis of well characterized, frozen samples of normal cervix, CIN I, CIN II and CIN III. Tiling resolution whole genome array comparative hybridization was used for the detailed investigation of lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). The efficacy of this tool was first confirmed in commonly used breast cancer cell lines and then in archival breast cancer tissue. RESULTS: This work has led to the identification of aberrations in a chromatin remodelling gene network not previously implicated in cervical intraepithelial neoplasia. Genomic copy number analysis revealed novel features not previously described including aberrations to multiple components of a single biological pathway (epidermal growth factor receptor), the delineation of alteration boundaries and the identification of a novel amplicon of prognostic significance in breast cancer. We identified novel copy number changes in several genes in LCIS and ALH (including HOXB cluster genes) that were used to elucidate a genomic signature. Aberrations in HoxB7 were identified in pre cancer lesions of both breast and cervix (LCIS and CIN III) tissue. CONCLUSION: Collectively, this work demonstrates that through whole genome approach of assessment of genomic copy number and expression we can identify novel genes and gene networks that are altered during the development of pre cancer lesions.
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