The use of mathematical and computational models to define the role of mutation and infection in colorectal cancer.
Date on Master's Thesis/Doctoral Dissertation
Ewald, Paul William
Cancer; JC Virus; infection; colorectal cancer; evolution; agent based model
Colon (Anatomy)--Cancer--Genetic aspects; Cancer cells--Mathematical models
Research over the past twenty five years has led to the development of the hypothesis that colorectal cancer is caused by the accumulation of mutations in tumor suppressor genes and proto-oncogenes. The last ten years has also revealed that the common JC Virus (JCV) is frequently found in colorectal tumors. This has led to the hypothesis that the virus, which is known to cause tumors in the lab, may playa role in colorectal cancer. However, the presence of JCV in colorectal tumors does not necessarily indicate a cause-effect relationship. Unlike in vivo and in vitro studies, mathematical and computational modeling provides an opportunity to evaluate the roles that mutation and infection play in colorectal tumorigenesis. Three probability models are developed to assess whether colorectal cancer can occur by mutation alone or if infection is required. Two models find that JCV is required for tumorigenesis, and that mutation alone is unable to generate any tumors. The third probability model finds the opposite; mutation is able to generate realistic numbers of colorectal cancer patients, while infection is not. All three models do indicate that selection for a stem cell mutation rate that is 100 times lower than transit cells provides protection from cancer, confirming the findings of other research groups. An agent based model is also developed to simulate many of the complexities that cannot be modeled in the probability models. The results from the agent based model indicate that ICV exacerbates colorectal cancer and greatly increases the risk of developing cancer. It also finds that mutation alone is able to cause colorectal cancer, although not as frequently as IC virus associated cases. All together, these models indicate that both mutation and infection have the capacity to drive tumorigenesis, but that the presence of IC Virus increases the risk of developing colorectal cancer. This strongly suggests that the role of ICV in colorectal cancer deserves more attention. If future studies confirm these findings, it would indicate that the prevalence of colorectal cancer can be reduced by taking measures to prevent infection by IC Virus.
Gatenbee, Chandler D. 1982-, "The use of mathematical and computational models to define the role of mutation and infection in colorectal cancer." (2012). Electronic Theses and Dissertations. Paper 481.