Identification of unique rectal cancer-specific subtypes

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Current colorectal cancer subtyping methods do not adequately account for distinct colon and rectal tissue expression profiles.
• Neoadjuvant chemoradiotherapy in rectal cancer significantly impacts gene expression, complicating existing subtyping approaches.

Purpose of the Study:

• To develop a rectal cancer-specific subtyping system (RSSs) that improves prognostic accuracy.
• To identify distinct molecular pathways within rectal cancer subtypes for targeted therapy development.

Main Methods:

• Analyzed mRNA expression profiles from 2121 rectal and colon cancer samples.
• Observed differential prognosis of Consensus Molecular Subtyping (CMS) in treatment-naïve rectal versus colon cancers.
• Clustered 182 untreated rectal cancers to establish rectal cancer-specific subtypes (RSSs) after confirming neoadjuvant chemoradiotherapy's impact on CMS.

Main Results:

• Identified three robust rectal cancer-specific subtypes (RSS1, RSS2, RSS3).
• RSS1 demonstrated better disease-free survival with high MYC target gene expression and low angiogenesis.
• RSS2 showed worse survival, characterized by low regulatory T cell abundance, strong EMT and angiogenesis signaling, and high TGF-β, NF-κB, and TNF-α signaling.
• RSS3 was defined by deactivated EGFR, MAPK, and WNT pathways.

Conclusions:

• Rectal cancer-specific subtyping (RSS) provides more accurate prognosis predictions than CMS.
• RSS subtyping offers novel insights into targetable disease pathways within rectal cancers.