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...

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Published in:Nature cancer Vol. 5; no. 11; pp. 1737 - 1753
Main Authors: Esplin, Edward D., Hanson, Casey, Wu, Si, Horning, Aaron M., Barapour, Nasim, Nevins, Stephanie A., Jiang, Lihua, Contrepois, Kévin, Lee, Hayan, Guha, Tuhin K., Hu, Zheng, Laquindanum, Rozelle, Mills, Meredith A., Chaib, Hassan, Chiu, Roxanne, Jian, Ruiqi, Chan, Joanne, Ellenberger, Mathew, Becker, Winston R., Bahmani, Bahareh, Khan, Aziz, Michael, Basil, Weimer, Annika K., Esplin, D. Glen, Shen, Jeanne, Lancaster, Samuel, Monte, Emma, Karathanos, Thomas V., Ladabaum, Uri, Longacre, Teri A., Kundaje, Anshul, Curtis, Christina, Greenleaf, William J., Ford, James M., Snyder, Michael P.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.11.2024
Nature Publishing Group
Subjects:
631/114
631/67
631/67/1504/1885/1393
Adenomatous Polyposis Coli - genetics
Adenomatous Polyposis Coli - pathology
Biomedical and Life Sciences
Cancer
Carcinogenesis - genetics
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Colon
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Female
Females
Gene Expression Profiling - methods
Gene Expression Regulation, Neoplastic
Hispanic Americans
Humans
Life Sciences
Lipids
Male
Metabolites
Mutation
Polyps
Precancerous Conditions - genetics
Precancerous Conditions - metabolism
Precancerous Conditions - pathology
Proteins
Proteomics
Proteomics - methods
Resource
Transcriptome
Tumorigenesis
ISSN:2662-1347, 2662-1347
Online Access:Get full text
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Summary: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. Snyder and colleagues present a comprehensive multiomic atlas of normal mucosal, benign polyps and dysplastic polyps from six persons with familial adenomatous polyposis, comprising transcriptomic, proteomic, metabolomic and lipidomic datasets.
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ISSN:2662-1347
2662-1347
DOI:10.1038/s43018-024-00831-z