Genetic "Shield" Lowers Colorectal Cancer Risk

A team of scientists from the Barbara Ann Karmanos Cancer Institute, Wayne State University, and institutions across the United States 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 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., president and chief executive officer 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., postdoctoral 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 reading it with DNA sequencing methods. To understand its role, the researchers engineered a special "humanized" mouse model carrying the genetic code and examined extensive genetic data from a global registry of human families. They discovered that having this specific genetic variation acts as 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 the 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.”

Reference: Johansen AM, Ziegler JT, Agyemang K, et al. TGFBR1*6A and Risk for Colorectal Cancer. Cancer Commun. 2026;46:0033. doi: 10.34133/cancomm.0033

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.