Abstract 4799: Variation in mutational landscape among small colonic polyps with differential growth rates

Abstract

Abstract Background: Benign adenomatous colonic polyps are transformed into cancers through the stepwise accumulation of mutations. However, not all polyps will progress. A significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and currently there are no biological characteristics that can reliably predict which polyps will grow or progress into invasive cancer. A multiancestral origin contributes to tumor heterogeneity and might provide additional growth promoting signals via increased genetic diversity. Methods: Utilizing a unique cohort of patients with small (<9mm) colorectal polyps in which growth was followed over a mean of 2.3 years by CT colonography, we performed next generation sequencing followed by micro-dissection and quantitative PCR to determine tumor origin. Results: The mutational landscape of small polyps is highly heterogeneous. Polyps carried 0 - 5 pathogenic mutations, with the most commonly altered gene being APC, which is considered the gatekeeper of the intestine. Interestingly, the percentage of cells harboring mutations in APC within a single polyp ranged from 2.0% to 70.6% with an average of 22.1%. In contrast, the frequency of a common APC single nucleotide polymorphism was 0% for non-carriers (n = 3), 55.9% for heterozygotes (n = 6), and 97.9% for homozygotes (n = 10). In the presence of an APC mutation, the average frequency of a second pathogenic mutation within a sample was 6.2% (n = 10). Conclusions: These data indicate that early intratumoral heterogeneity arising as a consequence of multiancestral origin affects tumor formation and growth. By determining the relative fitness advantage of heterogeneous polyps, we can begin to better predict which polyps may be more likely to progress into adenocarcinomas and which patients are predisposed to developing advanced disease. Citation Format: Chelsie K. Sievers, Perry J. Pickhardt, Kristina Matkowskyj, Dawn Albrecht, Luli Zou, David Kim, Meghan Lubner, Mark Reichelderfer, Richard Halberg. Variation in mutational landscape among small colonic polyps with differential growth rates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4799. doi:10.1158/1538-7445.AM2015-4799