Access Type

Open Access Dissertation

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Henry H. Heng

Second Advisor

Wayne D. Lancaster

Abstract

The dominant paradigm for cancer research focuses on the identification of specific genes for cancer causation and for the discovery of therapeutic targets. Alternatively, the current data emphasize the significance of karyotype heterogeneity in cancer progression over specific gene-based causes of cancer. Variability of a magnitude significant to shift cell populations from homogeneous diploid cells to a mosaic of structural and numerical chromosome alterations reflects the characteristic low-fidelity genome transfer of cancer cell populations. This transition marks the departure from micro-evolutionary gene-level change to macro-evolutionary change that facilitates the generation of many unique karyotypes within a cell population. Considering cancer cell populations to be complex-adaptive systems, multi-level analyses were performed longitudinally including whole genome microarray, population karyotype analysis, and determination of cell phenotype. As heterogeneity in ovarian cancer at each of these levels is linked to low survival, metastasis, and resistance to chemotherapy, a syngeinc model of spontaneous ovarian cancer development was employed. The significant findings of the current study are, 1) Genomic instability was apparent from the earliest stages of study, 2) Karyotypic heterogeneity was widespread, showed a pattern of expansion over time and preceded the acquisition of the transformed phenotype 3) a major karyotypic shift occurred between transformed cells in vivo and tumors formed in vitro, documenting the formation of a new system induced by environmental change 4) Chromosome copy number has greater impact on gene expression in early-stage cell populations, where karyotypes are beginning to depart from the diploid genome. A genome-centered paradigm for transformation is emphasized through the discovery of early large-scale increases in karyotype heterogeneity. This occurred well before the appearance of the transformed phenotype, arose much faster in Brca1 conditionally inactivated cells, was linked to the largest shift in gene expression, and was linked to the transition from in vitro to in vivo survival facilitating tumorigenesis. These data demonstrate the significance, methodologies and rationale for quantifying karyotype heterogeneity in transformation, tumorigenesis, and clinical cancers. Together, these findings support of a genome-centered evolutionary framework for cancer progression that emphasizes cell-to-cell genomic variability as the basis for macro-evolutionary selection and rapid phenotypic switching in response to new environments.

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