Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Genomics & Computational Biology

First Advisor

Carlo C. Maley

Abstract

Cancer is a disease that develops over decades as result of acquisition of abnormalities in the genomes of otherwise normal cells. Acquired genomic heterogeneity in populations of cells within tissues allows cell-level Darwinian evolution that selects abnormal cellular genotypes encoding neoplastic (new benign growth), and in some cases cancerous (invasion within tissues and metastasis across tissues) cellular phenotypes. I studied neoplastic evolution over time in vivo in the pre-malignant condition Barrett's esophagus to address the puzzling clinical phenomenon that 90-95% of individuals with Barrett's stay benign over decades compared to the remaining 5-10% who progress to esophageal adenocarcinoma. Some individuals with Barrett's use aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) that have been shown to reduce mortality from esophageal adenocarcinoma. I collaborated with the Seattle Barrett's Esophagus Research Program group to test the hypothesis that NSAIDs modulate genome evolution of neoplastic cells by reducing the acquisition rate of somatic genomic abnormalities (SGA). We used single nucleotide polymorphism (SNP) arrays to detect SGA, such as copy number abnormalities and loss of heterozygosity, in 161 biopsies from 13 individuals with Barrett's, obtained over 5-8 time points during 6-19 years of follow-up care. Over the follow-up period, each individual had a single change in NSAID use, allowing us to compare acquisition of SGA during periods on NSAIDs versus periods off NSAIDs within individuals. We found that the rate of accumulation of SGA was significantly lower (typically ten-fold lower) during periods on NSAIDs versus periods off NSAIDs. We also found that typically 1-3% of the genome had acquired SGA at baseline and that this percentage did not increase significantly over decades. In one individual who progressed to esophageal adenocarcinoma we detected a clonally expanded subpopulation of cells within the Barrett's tissue, which had massive SGA affecting 19% of the genome in the last 3 of 11 years of follow-up. In summary, these findings suggest that NSAID use may reduce SGA acquisition rate and that neoplastic cell populations in Barrett's can maintain evolutionary stasis over decades potentially explaining why 90-95% of individuals with Barrett's remain benign and never progress to esophageal adenocarcinoma.

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