TY - JOUR
T1 - Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis
AU - Esplin, Edward D.
AU - Hanson, Casey
AU - Wu, Si
AU - Horning, Aaron M.
AU - Barapour, Nasim
AU - Nevins, Stephanie A.
AU - Jiang, Lihua
AU - Contrepois, Kévin
AU - Lee, Hayan
AU - Guha, Tuhin K.
AU - Hu, Zheng
AU - Laquindanum, Rozelle
AU - Mills, Meredith A.
AU - Chaib, Hassan
AU - Chiu, Roxanne
AU - Jian, Ruiqi
AU - Chan, Joanne
AU - Ellenberger, Mathew
AU - Becker, Winston R.
AU - Bahmani, Bahareh
AU - Khan, Aziz
AU - Michael, Basil
AU - Weimer, Annika K.
AU - Esplin, D. Glen
AU - Shen, Jeanne
AU - Lancaster, Samuel
AU - Monte, Emma
AU - Karathanos, Thomas V.
AU - Ladabaum, Uri
AU - Longacre, Teri A.
AU - Kundaje, Anshul
AU - Curtis, Christina
AU - Greenleaf, William J.
AU - Ford, James M.
AU - Snyder, Michael P.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/9/30
Y1 - 2024/9/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85208061256&partnerID=8YFLogxK
U2 - 10.1038/s43018-024-00831-z
DO - 10.1038/s43018-024-00831-z
M3 - Article
C2 - 39478120
AN - SCOPUS:85208061256
SN - 2662-1347
VL - 5
SP - 1737
EP - 1753
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -
