Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Area of Science:

• Genetics
• Oncology
• Molecular Diagnostics

Background:

• MUTYH-associated polyposis (MAP) is caused by biallelic pathogenic variants (PVs) in the MUTYH gene.
• MAP shares phenotypic similarities with other hereditary colorectal cancer (CRC) syndromes, such as Familial Adenomatous Polyposis (FAP) and Lynch syndrome.
• Multi-gene hereditary cancer panel testing is increasingly utilized for diagnosing cancer predispositions.

Purpose of the Study:

• To characterize the phenotypic spectrum of MAP in individuals identified through multi-gene panel testing.
• To evaluate the diagnostic utility of panel testing for MAP, including cases not meeting traditional criteria.
• To compare the observed MAP phenotypes with existing literature and other hereditary CRC syndromes.

Main Methods:

• Retrospective review of genetic testing results and clinical histories from a commercial molecular diagnostic laboratory.
• Identification of individuals with biallelic MUTYH PVs detected via panel testing.
• Analysis of personal and family history, polyp burden, and occurrence of extracolonic cancers and other specific phenotypes.

Main Results:

• Biallelic MUTYH PVs were identified in 82 individuals (0.2% of tested population), with 91.5% having a history of CRC and/or polyps.
• 10% of individuals with reported polyps had fewer than 10, not meeting standard MAP testing criteria.
• Observed phenotypes included extracolonic cancers (25.6%), multiple primary cancers (23.2%), Lynch-like (20.7%), and FAP-like presentations (19.5%), alongside rare findings like mismatch repair-deficient tumors and sebaceous neoplasms.

Conclusions:

• Multi-gene panel testing is effective in identifying individuals with MAP, expanding the known phenotypic spectrum.
• MAP should be considered in the differential diagnosis for individuals with fewer than 10 polyps, depending on clinical context.
• The findings support broadening the consideration of MAP beyond typical indications, especially in individuals with suspected Lynch syndrome or FAP.