Abstract 2915: The timing of mutational burst events impact the growth of tumors in the colon

Basic and clinical scientists believe that benign polyps in the colon progress to cancers through the slow, stepwise accumulation of mutations. Interestingly, only a small percentage of all tumors progress, whereas a significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and mechanisms of tumor evolution during this premalignant phase are still under investigation and continued debate. We previously reported that sub-clonal diversity arises early in small human adenomas and contributes to the growth of tumors in the colon. An emerging hypothesis is that colorectal tumors form and progress via a process of punctuated equilibrium, where multiple copy number alterations and mutational events happen simultaneously in a burst-like fashion. In this study, we prospectively test this concept using a mouse model in which tumor induction is spatially and temporally controlled via a non-surgical delivery of adenovirus expressing CRE recombinase and a temporally controlled mutational burst via administration of the carcinogen Azoxymethane. Tumors are induced at a similar rate regardless the timing of the burst relative to tumor induction with a mean tumor incidence of 62% at three weeks post induction. However, tumor growth may be affected by the timing of the burst. Animals that had a mutational burst event prior to tumor induction or those that had a late mutational burst event had a lower average in vivo growth rate compared to controls and those with an early burst event, but the average in vivo tumor size was comparable across all groups. Taken together, these preliminary data provide evidence that the timing of a mutational burst event contributes to tumor growth. This prospective experiment is being extended through computer modeling and statistical inference to compare in silico mutational landscapes to a cohort of colon polyps removed from patients at normal screening. The findings will provide new insights into the earliest stages of tumorigenesis. Citation Format: Chelsie K. Sievers, Tien N. Vo, Perry J. Pickhardt, Bryan D. Pooler, Kristina A. Matkowskyj, Dawn M. Albrecht, Quincy Rosemarie, Michael A. Newton, Richard B. Halberg. The timing of mutational burst events impact the growth of tumors in the colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2915. doi:10.1158/1538-7445.AM2017-2915