Colorectal serrated pathway cancers and precursors

Area of Science:

• Gastroenterology
• Oncology
• Molecular Biology

Background:

• Colorectal cancer (CRC) arises through distinct pathways, including the conventional adenoma-carcinoma sequence and the serrated pathway (SP).
• The SP pathway is characterized by specific precursor lesions and molecular alterations.
• SP cancers exhibit unique biological behaviors and genetic profiles compared to conventional adenomas.

Purpose of the Study:

• To review the clinical impact, pathology, molecular genetics, and behavior of SP cancers.
• To summarize the clinicopathological features, classification, and molecular profiles of SP precursor lesions (SSA/P and TSA).
• To highlight the role of molecular mechanisms in SP lesion progression and their implications for CRC prevention.

Main Methods:

• Literature review focusing on clinical, pathological, and molecular aspects of the serrated pathway.
• Analysis of genetic mutations (RAS-RAF-MAPK pathway) and epigenetic modifications (CpG island methylation) in SP lesions.
• Classification of colorectal carcinomas based on their pathway of origin (SP vs. conventional).

Main Results:

• The SP pathway accounts for aggressive microsatellite stable (MSS) colorectal carcinomas.
• SP is also responsible for the majority of sporadic hypermutated, mismatch repair (MMR)-deficient, or microsatellite instable (MSI) colorectal carcinomas.
• Activating RAS-RAF-MAPK mutations and CpG island methylation are key drivers of SP lesion progression.

Conclusions:

• The serrated pathway represents a significant and distinct route to colorectal cancer development.
• Early identification and management of SP precursor lesions are critical for CRC prevention.
• Surveillance strategies for individuals with SP precursors offer opportunities to reduce CRC mortality.