Scientists Uncover a Genetic 'Shield' That Lowers the Risk of Colorectal Cancer

A team of scientists from the Barbara Ann Karmanos Cancer Institute, Wayne State University, and institutions across the U.S., have published a landmark paper on the role of TGFBR1*6A, a naturally occurring genetic mutation in the TGFBR1 gene found in approximately 14 percent of the general population.

The study, "TGFBR1*6A and risk for colorectal cancer," published online June 9, 2026, in Cancer Communications, a Science Partner Journal with an impact factor of 24.9, focuses on TGFBR1*6A and how it influences a person's risk of developing colorectal cancer. Boris Pasche, M.D., Ph.D., FACP, president and CEO of the Karmanos Cancer Institute and chair of the Wayne State University Department of Oncology, was the first to discover TGFBR1*6A as a cancer risk allele.

"This mutation has often been overlooked by genome-wide association study chips, which cannot detect TGFBR1*6A, and is commonly missed by next-generation sequencing platforms due to the complexity of the region," said Allan Johansen, Ph.D., MS, postdoctoral research fellow and first author of the paper. "In this study, we demonstrated that carriers of TGFBR1*6A have a reduced risk of developing colorectal cancer. This protective effect is even more pronounced in siblings of patients and in patients with familial adenomatous polyposis - a rare, inherited genetic condition that causes hundreds or more precancerous growths - called polyps - to form inside the colon and rectum. If left untreated, these polyps will inevitably turn into colorectal cancer, typically by around the age of 40."

For a long time, standard genetic sequencing tools overlooked this variant because of the difficulty in reading it with DNA sequencing methods. To understand its role, the researchers engineered a special "humanized" mouse model carrying this genetic code and examined extensive genetic data from a global registry of human families. They discovered that having this specific genetic variation acts like a natural shield, noticeably reducing the risk of colorectal cancer. Their findings could have significant implications for personalized patient care in the future.

Dr. Pasche shared the history and importance of the findings from this research.

"The journey began with the identification of TGFBR1*6A during my postdoc in Joan Massagué's lab in the late 1990s," he said. "Functional assessments showed that TGFBR1*6A transduced TGF-beta signals less effectively than its wild-type counterpart, TGFBR1. Early studies suggested that TGFBR1*6A may act as a colorectal cancer susceptibility allele; however, subsequent research by other groups did not confirm this association. Together with my long-time collaborator, Dr. Antonio Di Cristofano, we developed a mouse model of TGFBR1*6A by replacing the murine Tgfbr1 exon 1 with the human TGFBR1*6A or TGFBR1 exon 1. This model revealed that mice carrying the TGFBR1*6A allele developed fewer polyps and adenocarcinomas compared to those with two copies of the TGFBR1 allele."

In collaboration with the Colon Cancer Family Registry, the research team led by Dr. Pasche assessed the association of TGFBR1*6A with colorectal cancer risk among patients and their unaffected siblings. The findings were strikingly similar in humans, establishing TGFBR1*6A as a colorectal cancer protective allele. These exciting results are the culmination of years of work and support from the National Cancer Institute (NCI), the American Association for Cancer Research (AACR) and the American Cancer Society (ACS).

The research study was a collaborative effort that included Wayne State University faculty members Wael Sakr, M.D., also the dean of the School of Medicine, Ann Schwartz, Ph.D., Jennifer Beebe Dimmer, Ph.D., Lara Sucheston-Campbell, Ph.D., Asfar Azmi, Ph.D., Hugo Jimenez, Ph.D., and Greg Dyson, Ph.D., as well as collaborators from Wake Forest University and collaborators from the NCI-sponsored Colon Cancer Family Registry from the U.S., Canada, and Australia. Carl Langefeld, Ph.D., and Julie Ziegler at Wake Forest University did critical ancestry work that harnessed the strength of genome-wide association studies data from the Colon Cancer Family Registry, allowing for the integration of genetic background into the analysis.

This study was funded by the National Cancer Institute (NCI) (R01CA108741 and R01CA137000).

View the paper here.

Originally published by the Wayne State University Division of Research and Innovation.

Allan Johansen, Ph.D., MS

Boris Pasche, M.D., Ph.D., FACP