Risk Prediction of Metachronous Colorectal Cancer from Molecular Features of Adenomas: A Nested Case-Control Study.

Area of Science:

• Gastroenterology
• Oncology
• Molecular Pathology

Background:

• Current morphologic features for advanced adenomas (size, dysplasia, villous component) inadequately stratify risk for metachronous colorectal cancer (me-CRC).
• Suboptimal surveillance strategies arise from the inability to accurately distinguish high-risk from low-risk individuals.
• DNA copy-number alterations (CNAs) are implicated in adenoma-to-carcinoma progression.

Purpose of the Study:

• To evaluate if molecular features (CNAs) can better predict me-CRC risk compared to established morphologic features of advanced adenomas.
• To assess the prevalence of CNAs in advanced and non-advanced adenomas and their association with me-CRC.
• To inform optimized surveillance strategies for individuals with a history of adenomas.

Main Methods:

• A nested case-control study involving 529 individuals with a single adenoma from a Norwegian cohort.
• Low-coverage whole-genome sequencing to determine DNA copy-number profiles.
• Matching cases (me-CRC) with controls (no me-CRC) based on follow-up, age, and sex.

Main Results:

• CNAs associated with adenoma-to-carcinoma progression were found in 32% of advanced adenomas and 10% of non-advanced adenomas.
• me-CRC was significantly associated with age at baseline (OR, 1.14), advanced adenomas (OR, 2.46), and the presence of ≥3 DNA copy-number losses (OR, 1.90).
• While molecularly-defined high-risk adenomas showed association with me-CRC, the association of morphologically defined advanced adenomas was stronger.

Conclusions:

• Morphologic features of advanced adenomas remain a stronger predictor of me-CRC than CNA analysis alone.
• Current DNA CNA analysis does not independently improve me-CRC risk prediction.
• Further research is required to develop improved biomarkers and risk classification strategies for colorectal cancer surveillance.