Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Early detection of colorectal cancer (CRC) relies on understanding tumorigenesis.
• Biomarkers for rapidly progressing adenomas to CRC are poorly defined.

Purpose of the Study:

• To investigate mutational signatures in early colorectal adenomas.
• To identify potential biomarkers for aggressive adenoma progression.

Main Methods:

• Whole-genome sequencing (WGS) of adenoma tissue.
• Transcriptomic analysis.
• Immunohistochemical labeling for CEA and TGF-β signaling.

Main Results:

• High mutational profiles identified in colorectal adenomas.
• Distinct mutational signatures observed, dominated by C:G>T:A substitutions.
• Mutations in TGF-β and CEA-associated genes found in 4/11 adenomas.
• Increased CEA levels and loss of TGF-β signaling correlated in some adenomas.
• CEA B3 domain interaction with TGFBR1 identified, potentially inactivating TGF-β tumor suppressor function.

Conclusions:

• Diverse mutational processes drive adenoma to CRC transition.
• CEA and TGF-β pathway alterations are key in aggressive adenomas.
• Targeting CEA/TGF-β may enable early detection of high-risk colorectal adenomas.