Inherited Pancreatic Cancer-Risk Mutation Identified

Finding Could Spur New Targeted Treatments

Scientists have identified a rare inherited gene mutation that dramatically raises the lifetime risk of pancreatic and other cancers.

The discovery, reported in Nature Genetics by investigators from Dana-Farber/Brigham and Women’s Cancer Center, could lead to routine testing of individuals with a strong family history of pancreatic cancer to determine whether they carry the mutation, which occurrs in the gene known as RABL3. “There is evidence that catching pancreatic cancer through screening of high-risk individuals may improve outcomes,” said Sahar Nissim, MD, PhD, first author of the study.

About 10% of pancreatic cancers have a familial pattern, and in most cases the causative genetic flaw isn’t known. One inherited mutation that can predispose individuals to pancreatic cancer occurs in BRCA2, the gene that is also known to cause some breast and ovarian cancers.

The RABL3 mutation was pinpointed when scientists studied a family in which five relatives had pancreatic cancer and multiple family members had other cancers—a pattern suggesting an inherited mutation. The mutation accelerates the movement of a known pancreatic cancer protein, KRAS, within the cell. This alteration facilitates the placement of KRAS in the cell membrane and triggers a series of events that promote cancerous growth. Because KRAS activity is altered in a majority of pancreatic cancers, continued study of the RABL3 mutation’s impact on KRAS activity could provide important insights about pancreatic cancer development as well as a new strategy for targeted therapy, said the scientists.

The researchers emphasized that the RABL3 mutation is rare in the general population but said that testing for it may reveal the genetic predisposition in other families who have an unsolved hereditary cancer syndrome.

Source: Dana-Farber Cancer Institute, August 12, 2019