A new international study published in *Gastroenterology* suggests a more precise approach to assessing colorectal cancer risk may be within reach. Researchers have found that analyzing the DNA *within* colorectal polyps-rather than relying solely on customary blood tests-can reveal genetic mutations previously undetectable, offering crucial insights for improved diagnosis and treatment [[1]]. The findings are particularly significant for individuals with numerous polyps or a strong family history of the disease, where current genetic testing often returns inconclusive results.
Direct genetic analysis of colorectal polyps can reveal crucial information missed by traditional blood-based genetic testing, according to a new international study. The research, published in Gastroenterology, offers the potential to improve diagnosis, refine risk assessment, and guide clinical follow-up for individuals and their families.
Colorectal cancer is a common malignancy in Western countries and a leading cause of cancer-related deaths. While most cases develop sporadically, an estimated 5% to 10% are linked to inherited genetic factors – a percentage that rises significantly in younger patients. Identifying those with a genetic predisposition is vital for implementing early surveillance programs and reducing the incidence of advanced cancer.
Colorectal polyps, particularly when numerous, are considered precancerous lesions. Current clinical practice typically involves genetic testing of blood samples in individuals with at least ten polyps before age 60, or more than twenty before age 70. However, approximately three-quarters of these patients show no identifiable germline genetic alterations, despite clinical patterns suggesting a high hereditary risk.
“We often encounter patients with dozens of polyps or a clear family history of colorectal cancer, but whose standard genetic analysis comes back negative,” explained Richarda de Voer, a lead researcher at Radboudumc. “In these cases, we wanted to investigate whether studying the DNA directly from the polyps themselves could provide answers.”
Uncovering Previously Undiagnosed Genetic Mosaicism
The international team, working within the Solve-RD consortium, analyzed nearly 300 colorectal polyps from over 150 individuals with adenomatous or serrated polyposis, as well as patients with early-onset colorectal cancer, all of whom lacked known pathogenic germline variants. They used whole-exome sequencing to achieve this detailed analysis.
The results revealed a distinct pattern. Adenomatous polyps predominantly showed somatic mutations in the APC and CTNNB1 genes, key components of the WNT signaling pathway, while serrated polyps most frequently exhibited mutations in BRAF. A particularly significant finding was the identification of APC mosaicism in approximately 20% of individuals with adenomatous polyposis.
Mosaicism means the genetic alteration isn’t present in all cells of the body, but only in a portion, such as the intestinal tissue. “This predisposition isn’t detected in conventional blood tests, but can be identified by directly analyzing the polyps,” noted Stefan Aretz, a researcher at the University Hospital of Bonn. “Its detection has an important clinical impact, because it changes the interpretation of family risk.”
Unlike classic germline mutations, APC mosaicism doesn’t increase risk in siblings, although it can be passed on to offspring. Researchers suggest that systematically incorporating APC mosaicism analysis into clinical practice could lead to more precise genetic counseling and help avoid unnecessary screening for family members who aren’t at risk.
Serrated Polyps: Potentially Less Aggressive Than Thought?
The study also sheds new light on serrated polyps, a subtype whose potential to develop into cancer isn’t always clear. Nearly all serrated polyps analyzed presented with somatic mutations in BRAF, but, unlike adenomas, they exhibited a low mutational burden and a surprisingly similar molecular profile to normal colon tissue.
“Analysis of mutational signatures indicates that many BRAF-mutated serrated polyps behave, from a molecular standpoint, like an overgrowth of normal intestinal tissue,” De Voer explained. “This raises the question of whether all these polyps truly have the same potential for malignant transformation.”
Researchers observed that these polyps retain a mutational signature associated with healthy colon tissue, suggesting that the BRAF mutation may initiate the tumor process but isn’t sufficient on its own to drive aggressive malignant growth. This finding could have future implications for risk stratification and clinical decision-making, although the authors emphasize that further studies are needed to confirm which lesions will progress to cancer.
Clinical and Public Health Implications
In countries like the Netherlands, where approximately 12,000 people are diagnosed with colorectal cancer each year, population-based screening programs detect polyps and tumors at early stages. However, experts emphasize that more extensive genetic studies are only necessary in cases of extensive polyposis or alarm symptoms—such as digestive bleeding or unexplained abdominal pain.
The authors believe that incorporating advanced genetic analysis of polyps into routine European diagnostics could substantially improve care for patients with polyposis, providing diagnostic clarity, reducing uncertainty, and better tailoring follow-up strategies. This research highlights the importance of personalized medicine in cancer prevention.
“This approach not only benefits the patient, but also avoids unnecessary burden for their family members,” Aretz concluded. “Understanding the molecular origin of polyps is key to preventing colorectal cancer more effectively and personally.”
