APC mosaicism may explain unresolved polyposis cases

Some individuals with multiple colorectal adenomas do not receive a definitive genetic diagnosis after standard germline testing. Emerging evidence indicates that somatic mosaicism in the Adenomatous Polyposis Coli (APC) gene may explain a portion of these cases, offering opportunities to improve genetic testing approaches and tailor surveillance strategies in clinical practice.

In a multi-center cohort of 541 patients with colorectal adenomas or carcinomas — many without a known germline cause — APC mosaicism was detected in 9.4% of cases using targeted next-generation sequencing of tumor tissue, according to research published in Gastroenterology. Detection rates differed by clinical presentation, reaching 14.3% among patients who met criteria for hereditary polyposis testing, compared with 2.3% among those who did not meet guideline thresholds.

The findings highlight a potential explanation for patients with polyposis who test negative on routine genetic panels, ntoed Diantha Terlouw, PhD, and colleagues. Familial adenomatous polyposis (FAP) is typically driven by germline APC variants, but mosaicism — where pathogenic variants are present in only a subset of cells — may account for some otherwise unexplained cases. 

APC mosaicism was more commonly detected in patients with a higher adenoma burden, particularly those with at least 20 adenomas before age 60 or at least 30 adenomas before age 70, where detection rates were 10% or higher. Detection was also higher among patients who met hereditary polyposis testing criteria than among those who did not, noted Dr. Terlouw of the Department of Pathology at Leiden University Medical Center in the Netherlands, and colleagues.

Overall colorectal cancer rates were similar between groups, but mosaic patients who developed cancer did so at a younger age. Extracolonic manifestations appeared less frequent, although upper gastrointestinal involvement remained clinically relevant. Among patients who underwent esophagogastroduodenoscopy, 26% had gastric or duodenal polyps. 

"The frequency of additional endoscopies should depend on the findings. Furthermore, despite the low chance of transmission, we recommend considering germline testing in children of mosaic cases," noted the researchers.

Based on these findings, the authors proposed refining testing thresholds to improve detection. In patients with negative germline testing, APC mosaicism testing may be appropriate in those with 20 or more adenomas before age 60 or 30 or more adenomas before age 70, where detection rates exceed 10%. 

For management, surveillance strategies broadly aligned with attenuated FAP are suggested. This includes regular colonoscopy, with frequency guided by findings, and at least one upper endoscopy.

Mosaicism has implications for family members, although transmission risk appears to be low. None of the children tested in this cohort were found to carry the variant. However, transmission cannot be excluded. In one case, the variant was detected in semen, indicating the potential for germline transmission. Genetic testing in offspring may therefore be considered, noted researchers.

The study also identified “hybrid” cases, in which some, but not all, lesions shared the same APC variant. These cases, observed in 21% of one cohort, were phenotypically similar to nonmosaic patients and may reflect alternative mechanisms, such as environmental mutational processes or clonal relationships between lesions. This variability highlights the need for cautious interpretation, as not all mosaic-like findings carry the same clinical implications. 

Follow-up was limited, leaving uncertainty around long-term cancer risk, extracolonic disease, and transmission rates. Testing approaches also varied across centers, and mosaicism confined to specific tissues may have been missed. Further work is needed to refine testing thresholds, clarify risk stratification, and determine whether surveillance can be tailored based on mosaic patterns. 

Overall, APC mosaicism appears to be a clinically relevant and underrecognized contributor to unexplained polyposis. In patients with moderate-to-high adenoma burden who test negative for germline variants, targeted mosaicism testing may improve diagnostic yield and provide a clearer basis for surveillance and family counseling. 

The authors reported no conflicts of interest.