Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists.

Area of Science:

• Genetics
• Gastroenterology
• Oncology

Background:

• Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are known colorectal polyposis syndromes.
• A significant proportion of adenomatous and serrated polyposis cases remain genetically unexplained.
• Accurate genetic diagnosis is crucial for patient management and risk stratification.

Purpose of the Study:

• To investigate unexplained colorectal polyposis cases for underlying genetic defects.
• To evaluate the utility of complementary genetic testing for APC and MUTYH genes.
• To screen candidate genes involved in Wnt and TGF-β pathways for germline mutations.

Main Methods:

• Included patients with >40 adenomas or >20 serrated polyps without identified causative mutations.
• Performed complementary APC and MUTYH analyses, including mosaicism and large genomic rearrangements.
• Screened Wnt pathway genes (AXIN2, PPP2R1B, WIF1, SFRP1) and TGF-β pathway genes (SMAD4, BMPR1A) for germline mutations.

Main Results:

• Identified pathogenic mutations in 5/25 patients with unexplained adenomatous polyposis (4 in APC, 1 in BMPR1A).
• Detected a SMAD4 frameshift mutation in 1/13 patients with unexplained serrated polyposis.
• All identified mutations occurred in familial cases; BMPR1A and SMAD4 cases were reclassified as juvenile polyposis.

Conclusions:

• Causative mutations were identified in 17% (6/38) of unexplained polyposis patients, demonstrating heterogeneous genetic causes.
• APC mosaicism should be considered in sporadic polyposis.
• Accurate histological classification is critical for guiding genetic testing in polyposis syndromes.