Our current theory of neoplastic progression specifies that clones arise through genetic or epigenetic instability, and if they have a reproductive or survival advantage over other cells in the neoplasm, within their microenvironment, they will expand in the neoplasm in a selective sweep. Thus, we believe neoplastic progression is characterized by a series of selective sweeps. However, virtually all data on that process to date is cross-sectional, with observations of genetic diversity and large clonal expansions within neoplasms at a single time point. I will describe data that, for the first time, tracks the evolutionary dynamics of clones in a solid neoplasm over time. We have analyzed the frequency of large clonal expansions, the rate of those expansions and changes in clonal diversity over time in a cohort of 174 patients with Barrett’s esophagus. Barrett’s esophagus is a premalignant condition that predisposes to the evolution of esophageal adenocarcinoma. Unlike most other premalignant neoplasms, the Barrett’s tissue is not resected upon detection due to significant mortality and morbidity associated with esophagectomies. Instead, serial endoscopic surveillance for the early detection of cancer is the recommended management of the condition. This allows us to study neoplastic progression over both space and time in unprecedented detail. In the Seattle Barrett’s Esophagus Project, we also gather data on host and environmental factors that may impact progression, including use of non-steroidal anti-inflammatory drugs, which have been associated with a dramatic reduction of risk for progression to cancer. I will relate the factors associated with clonal expansions and genetic diversity to the parameters that determine the rate of evolution: mutation rate, population size, stem cell generation time and the fitness effects of mutations.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN12-01.
Seventh AACR International Conference on Frontiers in Cancer Prevention Research-- Nov 16-19, 2008; Washington, DC