Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.
Competing Interests: Competing interests: M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, v Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, NextThought and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza, Mitrix, Yuvan, TranscribeGlass and Applied Cognition. A. Kundaje has affiliations with Biogen (consultant), SerImmune (scientific advisory board (SAB)), RavelBio (scientific cofounder and SAB) and PatchBio (SAB). K.C. is currently an AstraZeneca employee. W.J.G. has affiliations with Guardant Health (consultant and SAB), Protillion Biosciences (scientific cofounder) and 10x and has licenced patents associated with ATAC-seq. E.D.E. is an employee and stockholder of Labcorp, and advisor and stockholder of Taproot Health, Exir Bio and ROMTech. The other authors declare no competing interests.
(© 2024. The Author(s).)