Cancer is a disease of somatic evolution. Random mutations that arise during life and confer a growth advantage upon a cell will preferentially multiply to form a tumor. This dissertation considers some of the implications of clonal evolution in cancer with an emphasis on how the evolutionary process, itself, facilitates disease progression and how its signature can be clinically used for early disease detection. The first part introduces the subject of mutations in cancer within an evolutionary context and discusses the origins and consequences of genetic heterogeneity in developing neoplasms. The second part describes experimental studies on clonal evolution of two distinct varieties. In the first study, somatic mutations in mutational hotspots are used to detect preneoplastic clonal expansions in the colons of patients with the cancer-predisposing disease, ulcerative colitis (UC). The results show that clones within non-dysplastic UC tissues are strongly correlated with cancer progression elsewhere in the colon and are potentially a biomarker of future cancer development risk. The second study describes competition experiments among E. coli strains with differing mutations rates as a model of competition among genetically unstable tumor cells. The results show that an optimal mutation rate exists for cells competing under specific conditions and that deviation in either direction from this optimum is detrimental to evolvability. The findings suggest that targeting mutation rate may be one means by which the evolutionary process of cancer progression can be delayed. Together this work contributes to the growing body of knowledge of the significance of clonal evolution in cancer and lays the groundwork for future studies to translate these findings into clinical tools and treatments.
|Advisor:||Loeb, Lawrence A.|
|School:||University of Washington|
|School Location:||United States -- Washington|
|Source:||DAI-B 71/10, Dissertation Abstracts International|
|Subjects:||Genetics, Evolution and Development, Pathology, Oncology|
|Keywords:||Cancer, Clonal evolution, Disease detection, Genome, Mutation, Ulcerative colitis|
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