Imagine facing a potential cancer risk, only to have standard genetic tests come back negative. It's a frustrating reality for many families with a history of colorectal cancer. But what if the answer lies not in your blood, but within the very polyps themselves? That's the question a groundbreaking new study is tackling, and the implications could change how we approach genetic screening for this disease.
It's understood that genetics play a role in roughly 5% to 10% of all colorectal cancer cases. What's particularly striking is that this hereditary link seems to be more prevalent in younger individuals who are diagnosed. Colorectal polyps are often considered potential stepping stones to cancer, especially when someone develops a significant number of them. For example, if someone under 60 has at least 10 polyps, or if someone under 70 has more than 20, doctors often recommend genetic testing via blood DNA analysis. This testing can pinpoint a genetic cause in about 25% of these cases. When a specific gene mutation is found, the patient and their relatives who also carry the mutation can then undergo regular screenings, allowing for early detection and treatment of colorectal cancer. This is incredibly important as earlier detection often leads to better outcomes.
But here's where it gets controversial... What about the other 75%? In a significant number of cases, even when there's a strong suspicion of a hereditary risk (based on family history and polyp count), standard blood tests fail to identify any genetic cause. Why does this happen? A team of European researchers decided to dig deeper, and their findings, published in the journal Gastroenterology, are truly eye-opening. (https://www.sciencedirect.com/science/article/pii/S0016508525061347?via%3Dihub)
Dr. Richarda de Voer, an Associate Professor of Cancer Genomics at the Radboud University Medical Center and co-lead author of the study, explains their approach: "In these cases where blood tests were inconclusive, but the suspicion of a genetic link remained high (due to a large number of polyps or family history), we performed extensive genetic analysis directly on the DNA from the polyps themselves. Our goal was to see if this could give us a clearer picture of how these polyps develop and if there was a genetic component we were missing."
And this is the part most people miss... The researchers, working as part of the Solve-RD consortium, analyzed 333 polyps from 180 individuals across Europe. All these individuals had a strong suspicion of hereditary colorectal cancer, but their blood-based genetic tests came back negative. What they found was remarkable: Approximately 80% of the individuals had adenomatous polyps. These polyps were primarily caused by non-hereditary mutations in the APC gene. However, and this is crucial, in at least 20% of these individuals, they discovered APC mutational mosaicism. What exactly does that mean? It means that the genetic predisposition wasn't present in all the cells of the body, but rather restricted to certain cells, such as those in the large intestine. Think of it like a mosaic tile pattern—the mutation is only present in some tiles, not the entire picture.
Dr. Stefan Aretz, a co-lead researcher from the University of Bonn, points out that while the existence of this predisposition has been known for some time, it's not yet routinely tested for across all centers in Europe. The study also suggests that APC is likely the only gene where mosaicism plays a significant role in the development of adenomatous polyps without a clear hereditary predisposition. What are the implications of this? Dr. De Voer explains: "If a blood test is negative, DNA analysis of polyps is the way to detect this form of genetic predisposition. It's important because while siblings of someone with this form of predisposition are not at increased risk, their offspring may be." In other words, standard family screening might miss this critical piece of information. Furthermore, the study is providing valuable insights into the early genetic and epigenetic mechanisms of tumor formation in the gastrointestinal tract, which could lead to even more targeted prevention strategies in the future.
Interestingly, the study also looked at so-called serrated polyps in about sixty individuals. Almost all of these polyps showed a non-hereditary mutation in the BRAF gene. Detailed genetic analysis indicated that these polyps genetically resembled an overgrowth of normal intestinal tissue. However, Dr. De Voer cautions that further research is needed to determine whether these polyps will always develop into colorectal cancer.
The bottom line? These findings strongly suggest that DNA analysis of polyps, using advanced technologies, should become a standard part of diagnostics. As Dr. Aretz concludes, identifying APC mosaicism through a more comprehensive work-up in routine care not only provides diagnostic clarity for patients but also relieves anxiety for their relatives and can rule out risk in the majority of their children.
This study raises some important questions. Should polyp DNA testing become a routine part of colorectal cancer screening, even when blood tests are negative? How will healthcare systems adapt to incorporate this more complex and potentially more expensive testing? Could this approach be applied to other types of cancer where hereditary links are suspected but difficult to confirm? Share your thoughts and opinions in the comments below!
DISCLOSURE: For full disclosures of the study authors, visit sciencedirect.com (https://www.sciencedirect.com/science/article/pii/S0016508525061347?via%3Dihub) .
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
