DNA Testing of Colorectal Polyps Improves Insight into Hereditary Risks

Individuals with large numbers of colorectal polyps are often suspected of having an inherited cancer risk, yet standard blood-based genetic testing fails to identify a cause in most of them. This uncertainty complicates decisions about surveillance and raises concerns for family members. New research now shows that analyzing the DNA of the polyps themselves can reveal hidden genetic mechanisms and clarify cancer risk.

In the study led by Radboud University Medical Center (Nijmegen, Netherlands), in collaboration with University Hospital Bonn (Bonn, Germany), researchers focused on patients with many colorectal polyps who showed no inherited mutations in blood-derived DNA. Instead of relying solely on blood tests, the team applied advanced DNA sequencing techniques directly to polyp tissue to better understand how these lesions arise and progress.

Within the international Solve-RD consortium, the researchers examined 333 colorectal polyps from 180 individuals across Europe. All participants had a strong clinical suspicion of hereditary risk but negative results from conventional genetic testing. By analyzing somatic mutations and mosaic patterns within polyp DNA, the team aimed to uncover predispositions that are confined to intestinal tissue and therefore invisible in blood samples.

The analysis revealed two major patterns. In patients with adenomatous polyps, most lesions were driven by non-hereditary mutations in the APC gene, but at least 20% showed APC mutational mosaicism, meaning the genetic predisposition was limited to certain tissues. In patients with serrated polyps, almost all lesions carried non-hereditary BRAF mutations and closely resembled overgrowth of normal intestinal tissue.

The findings, published in Gastroenterology, demonstrate that DNA analysis of colorectal polyps provides clinically relevant information beyond standard blood testing. Identifying APC mosaicism can refine risk prediction, guide surveillance strategies, and clarify which relatives are truly at risk. The approach also offers new insight into early genetic and epigenetic events in colorectal tumor development. Researchers advocate incorporating polyp DNA analysis into routine diagnostics for patients with multiple polyps.

“If a blood test is negative, DNA analysis of polyps is the way to detect this form of genetic predisposition,” said Richarda de Voer, lead researcher at Radboud UMC. “This provides diagnostic clarity for patients and helps determine which family members require monitoring and which do not.”

Related Links:
Radboud UMC
University Hospital Bonn