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.
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.
Introduction: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with poor prognosis and limited treatment options. While ICC has traditionally been considered a malignancy of biliary epithelial cells, increasing evidence suggests that hepatocytes can...
Introduction: Liver fibrosis is the key determinant of long-term outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) drive fibrogenesis, but effective antifibrotic therapies remain unavailable. This study investigated whether blocking the succinate–GPR91...
Introduction: The progression from metabolic dysfunction-associated fatty liver (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex interactions between hepatocytes and immune cells. This study identifies a novel spatial mechanism in the periportal (PP)...
Introduction: Cardiovascular–Kidney–Metabolic (CKM) syndrome recognizes the close interaction between obesity, type 2 diabetes, chronic kidney disease, and cardiovascular disease. This review highlights the emerging role of the gut microbiome, particularly butyrate-producing bacteria, as a central...
• Small intestinal adenocarcinoma (SIA) is a rare gastrointestinal cancer with limited disease-specific prognostic biomarkers and generally poor outcomes. • This nationwide Dutch population-based study evaluated whether three routinely available immunohistochemical markers—CK7, CK20, and CDX2—have...
Introduction: Metabolic dysfunction–associated steatotic liver disease (MASLD) is closely linked to insulin resistance and type 2 diabetes, with the liver traditionally viewed as a key regulator of blood glucose through hepatic glucose production. However, emerging...
We are pioneers in clinical intelligence, dedicated to helping gastroenterologists harness the power of artificial intelligence to drive precision, efficiency, and patient growth.