Abstract A005: APC mutations dysregulate alternative polyadenylation in cancer

Abstract

Abstract Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We completed an unbiased computational analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identified that colorectal adenocarcinoma is distinct from all other cancer subtypes. We linked this distinction to the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which were strongly associated with expression of long 3′ UTRs relative to tumors lacking APC mutations. APC knockout similarly dysregulated APA in human colon organoids, and reduced APC expression was associated with APA dysregulation in tumor types lacking APC mutations. Building on previous work that identified APC as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, we found that APC binding is most significantly enriched just upstream of proximal poly(A) sites within 3′ UTRs. Our results suggest that APC promotes proximal poly(A) site use and that APC loss contributes to pervasive APA dysregulation in human cancers. Citation Format: Austin M Gabel, Andrea E Belliville, James D Thomas, Jose Mario B Pineda, Robert K Bradley. APC mutations dysregulate alternative polyadenylation in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A005.