It is estimated that hereditary factors play a role in about 5% to 10% of colorectal cancer cases, with a higher prevalence of hereditary factors seen in younger patients. Many colorectal polyps are considered potential precursors to cancer: at least 10 polyps in individuals younger than 60 years and more than 20 in those younger than 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-quarters of patients, no genetic cause of the disease can be uncovered, even when there is strong suspicion of hereditary risk. To ascertain why, a European group performed extensive testing on these individuals; Sommer et al reported their results in Gastroenterology.
Co-lead study author Richarda de Voer, PhD, an Associate Professor of Cancer Genomics at the Radboud University Medical Center, explained, “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.”
Findings
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 for colorectal cancer detected by analysis from blood-derived DNA. A clear picture emerged: about 80% of individuals had adenomatous polyps; these polyps were mainly caused by nonhereditary mutations in the APC gene, but in at least 20% of individuals, there was APC mutational mosaicism, meaning that the predisposition was 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,” said Stefan Aretz, PhD, co-lead researcher and member of the Transdisciplinary Research Area “Life & Health” at the University of Bonn. Furthermore, the findings of this study suggest 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,” Dr. De Voer added. Moreover, the study provided valuable insights into the early genetic and epigenetic mechanisms of tumor formation in the gastrointestinal tract.
Additionally, about sixty individuals in the study had so-called serrated polyps; almost all of these showed a nonhereditary mutation in the BRAF gene. Detailed genetic analysis revealed that these polyps genetically resembled an overgrowth of normal intestinal tissue. Dr. De Voer commented, “We want to investigate this further, because at this point, we cannot say whether these polyps will always develop into colorectal cancer.”
These findings demonstrate the added value of making DNA analysis of polyps using advanced technologies a standard part of diagnostics. “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,” concluded Dr. Aretz.
DISCLOSURE: For full disclosures of the study authors, visit sciencedirect.com.
