DNA testing of colorectal polyps improves insight into hereditary risks

In about 5–10% of colorectal cancer patients, hereditary factors play a role, with higher percentages among younger patients. Research from Radboud university medical center and university hospital Bonn (UKB) in collaboration with researchers from Munich and Barcelona, shows that DNA analysis of colorectal polyps provides important additional information on the development of these polyps and colorectal cancer. This DNA analysis leads to better diagnostics and treatment and offers patients and their family members greater clarity. The results have now been published in Gastroenterology.

Colorectal cancer is one of the most common cancers in the Western world (WHO fact sheet). It is estimated that hereditary factors play a role in about 5–10% of these cases, with a higher prevalence of hereditary factors in younger patients. A large number of colorectal polyps are considered potential precursors to cancer: at least 10 polyps in people under 60 and more than 20 in those under 70. These individuals can undergo genetic testing through blood DNA analysis. In about one-quarter of cases, a genetic cause is identified. These patients and the mutation carriers among their relatives qualify for regular screenings to detect and treat colorectal cancer at an early stage.

However, in the remaining three-quarter patients, no genetic cause of the disease can be uncovered, even when there is strong suspicion of hereditary risk, explains Richarda de Voer, lead researcher at Radboudumc. “For example, because they have a large number of polyps or relatives diagnosed with colorectal cancer. In this group, we performed extensive genetic analysis on the DNA of the polyps themselves. We wanted to know whether this could provide more information, such as how a polyp develops.”

Risk prediction 
Together with an international team within the Solve-RD consortium, the research groups analyzed 333 polyps from 180 individuals across Europe who had no genetic cause detected by analysis from blood-derived DNA. A clear picture emerged. Eighty individuals had adenomatous polyps. These polyps were mainly caused by non-hereditary mutations in the APC gene, but in at least 20% of individuals, there was APC mutational mosaicism. This means that the predisposition is not present in all body cells, but for example, restricted to cells of the large intestine.

“We already know for some time that this predisposition for polyps and colorectal cancer exists, but it is not yet routinely analyzed across all centers in Europe,” says Stefan Aretz, lead researcher and member of the Transdisciplinary Research Area “Life & Health” at the University of Bonn. Furthermore, this study suggests that in the development of adenomatous polyps without hereditary predisposition, APC is likely the only gene where mosaicism plays a role. “If a blood test is negative, DNA analysis of polyps is the way to detect this form of genetic predisposition. This is important because siblings of someone with this form of predisposition are not at increased risk, but their offspring may be” De Voer completes. Moreover, the study provided valuable insights into the early genetic and epigenetic mechanisms of tumor formation in the gastrointestinal tract.

Growth from normal tissue? 
About sixty individuals had so-called serrated polyps. Almost all of these showed a non-hereditary mutation in the BRAF gene. Detailed genetic analysis revealed that these polyps genetically resemble an overgrowth of normal intestinal tissue. De Voer: “We want to investigate this further, because at this point, we cannot say whether these polyps will always develop into colorectal cancer.”

Clarity in diagnosis 
With this research, the teams from De Voer, Aretz, and their colleagues have provided clarity to a large group of patients, demonstrating the added value of making DNA analysis of polyps using advanced technologies a standard part of diagnostics in Europe. “In particular the identification of APC mosaicism due to the implementation of a more comprehensive work-up in routine care enables not only diagnostic clarity to the patients but relieves their relatives and can exclude a risk in the majority of their children”, said Aretz. 

When is further testing needed? 
In the Netherlands, about 12,000 people are diagnosed with colorectal cancer each year. Everyone aged 55 to 75 receives an invitation for colorectal cancer screening every two years. Participation is voluntary and helps detect cancer early. If follow-up tests reveal a few polyps (e.g., 2 or 3), this usually does not indicate a substantially increased risk. Only in cases of numerous polyps (10 under age 60 or 20 under age 70) or symptoms such as unexplained abdominal pain or blood in the stool may additional testing be necessary. If you are unsure or have symptoms, always contact your GP.