APCmutations dysregulate alternative polyadenylation in cancer

Background: Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. Results: We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APCmutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APCmutations. APCknockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APCexpression is associated with APA dysregulation in tumor types lacking recurrent APCmutations. Conclusions: As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.