Some genetic variations may do the opposite of what scientists once expected—not increase disease risk, but reduce it. This is the conclusion of an international team of researchers from the Barbara Ann Karmanos Cancer Institute, Wayne State University, and other U.S. research institutions, who investigated a rare variant of the TGFBR1 gene known as TGFBR16A. Their findings were published in the journal Cancer Communications.

The genetic variant is present in approximately 14% of the population and has remained relatively understudied for many years. One reason is that many modern genetic testing methods either fail to detect it accurately or overlook it entirely because of the complexity of the DNA region where it occurs.

The researchers found that carriers of TGFBR16A have a lower risk of developing colorectal cancer. The protective effect was particularly pronounced among individuals with a family history of the disease, including relatives of colorectal cancer patients and people with Familial Adenomatous Polyposis, a rare inherited condition characterized by the development of hundreds of intestinal polyps that often progress to cancer at a young age.

According to Dr. Boris Pasche, President and CEO of the Karmanos Cancer Institute and Chair of Oncology at Wayne State University, this gene variant had long been viewed as a possible risk factor. However, the new evidence points in the opposite direction.

To test their hypothesis, the research team employed multiple approaches, including analyses of large colorectal cancer family registries and the creation of a “humanized” mouse model in which the mouse TGFBR1 gene was replaced with human gene variants.

The results were remarkably consistent. Mice carrying the TGFBR16A variant developed fewer polyps and tumors than animals with the standard version of the gene. A similar pattern was observed in the human clinical data.

The authors emphasize that the mutation affects signaling through the transforming growth factor-beta (TGF-β) pathway, a critical biological system involved in regulating cell growth and tissue development. In carriers of TGFBR16A, signaling through this pathway appears to be less efficient, which may reduce the likelihood of abnormal tissue growth and tumor formation.

Historically, the genetic variant was first described in the late 1990s by Boris Pasche during his fellowship in the laboratory of Joan Massagué. However, subsequent studies produced conflicting results, leaving its role uncertain for decades.

The new study, which combines data from international familial cancer registries with experimental animal research, is the first to consistently demonstrate a protective effect associated with this genetic variant.

The researchers believe the findings could have important implications for personalized medicine. In the future, a patient's genetic profile may be used not only to identify risk factors but also to detect naturally occurring protective genetic traits that help guard against disease.