Understanding Polyposis Development: Gastroenterology | March 26

Introduction

Most clinicians recognise classic inherited polyposis syndromes such as familial adenomatous polyposis (FAP) from pathogenic variants in APC, and MUTYH-associated polyposis (MAP) from biallelic MUTYH variants. Yet, a large proportion of patients with 20–100 adenomas (and even some with hundreds) remain “genetically unexplained” after routine multigene panel testing. This editorial discusses why that gap persists and why newer molecular approaches are beginning to close it.

Summary

Llor reviews major advances that explain previously unresolved polyposis cases. A key theme is that many APC pathogenic alterations are missed by standard testing, including deep intronic variants causing aberrant splicing or pseudoexon formation, synonymous changes that disrupt splicing, large structural rearrangements, and mobile element insertions—often requiring whole-exome/genome sequencing, long-read sequencing, and RNA-based analyses for detection. Another important mechanism is somatic mosaicism, where post-zygotic APC mutations are present only in a subset of tissues; phenotype depends on when the mutation occurs in development and can appear attenuated in the proband but become more severe in offspring if transmitted through germline involvement. Mosaic APC variants may account for a meaningful fraction of “unexplained” FAP-like presentations.

The editorial highlights new work by Sommer et al. in this issue, who studied individuals with unexplained adenomatous or serrated polyposis and found APC mosaicism in ~19% of evaluable adenomatous polyposis cases, with additional suspected mosaicism. The broader implication is practical: when multigene panels are negative, clinicians and genetic services should increasingly consider expanded diagnostics that include intronic/regulatory APC alterations and mosaicism testing.

Finally, Llor notes that serrated lesions show distinct molecular patterns (often BRAF), but their biology may not mirror adenomatous APC-driven progression; many serrated lesions may represent benign clonal outgrowths requiring additional hits to progress—an area where major mechanistic questions remain.