role of heterozygous apc mutation in niche succession and initiation of colorectal cancer – a computational study杂合的apc基因突变在利基继承和结肠直肠癌的起始u2014u2014计算研究.pdfVIP

Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study Roschen Sasikumar*, John Raji Rejitha, Ponthananiyil Kumaran Binumon, Muraleedharan Manoj Computational Modeling and Simulation Group, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum, Kerala, India Abstract Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP) have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC+/ 2 stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding