# Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality

## TL;DR

This review explores how FAP adenomas form and evolve, aiming to guide new prevention strategies for this hereditary cancer syndrome.

## Contribution

The paper provides new insights into the competition and cooperation dynamics of mutant cells in FAP adenoma development.

## Key findings

- Mutant cells expand and compete with normal cells in intestinal crypts.
- Multiple mutant crypts cooperate to form polyclonal adenomas.
- Polyclonal lesions transition to monoclonality as adenomas progress to cancer.

## Abstract

Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum. Prophylactic surgery remains the primary intervention strategy, as there are currently no pharmacological treatment options for FAP patients. Previous therapeutic approaches have predominantly focused on reducing polyp size rather than preventing their initiation, thereby missing a key opportunity for early intervention. Crucially, to effectively target the earliest stages of tumour development requires a deeper understanding of the molecular mechanisms underlying adenoma formation. In this review, we evaluate the latest models and methods employed to investigate the origin of FAP adenomas. We describe how mutant cells expand from their initial emergence within the intestinal epithelium and how they compete with normal cells within intestinal crypts. In addition, we discuss how multiple mutant crypts cooperate to collectively form polyclonal adenomas, and how these polyclonal lesions gradually transition towards monoclonality as adenomas progress towards colorectal cancer. Finally, we highlight how these insights inform the development of targeted cancer prevention strategies for individuals with FAP.