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Study Identifies Gene Mutation (in RABL3 Gene) Linked to Hereditary Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers with limited treatment options. It typically comes with an especially poor prognosis due to its lack of symptoms until advanced stages and its ability to resist many anticancer therapies. Identifying genes involved in its development may lead to earlier diagnoses and improved treatments. Now, a research team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women's Hospital, and Dana-Farber Cancer Institute has found that a mutation in a particular gene is associated with hereditary forms of pancreatic cancer in one family studied. Approximately 10% of pancreatic cancer is believed to be hereditary (see discussion of pancreatic cancer in former US President Jimmy Carter's family below). The research group also uncovered a mechanism by which mutations such as the one they identified may contribute to the development of tumors. In their study, which was published online on August 12, 2019 in Nature Genetics, the researchers sequenced the genomes of a family in which multiple members had pancreatic cancer. The analyses revealed a mutation in the RAS oncogene family-like 3 (RABL3) gene. The article is titled “Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer.” To assess the effects of this gene mutation, the investigators recapitulated it in zebrafish, a model which offers large populations for studying the impact of newly discovered genetic mutations on cancer risk. The fish carrying the mutation developed cancers at an accelerated rate and with greater frequency. Additional studies revealed that the protein expressed by RABL3 interacts with components of the RAS signaling pathway, which has been implicated in various forms of cancer and other conditions. Because aberrant RAS pathway signaling is found in most pancreatic cancers, research into how RABL3 impacts the RAS pathway could offer new strategies for targeted therapy.

"This work is a prime example for 'bedside-to-fish tank and back,' where we start with a patient story and their family history, and use genetic methods to identify a gene mutation that we then confirm in the zebrafish model to ultimately discover novel diagnostic tests and targets for potential therapy," said senior author Wolfram Goessling, MD, PhD, Chief of the Division of Gastroenterology at MGH.

The findings may also provide an explanation for other families with multiple cases of pancreatic cancer, noted lead author Sahar Nissim, MD, PhD, a cancer geneticist and gastroenterologist at the Dana-Farber Cancer Institute and Brigham and Women's Hospital.

"More broadly, this work highlights the power of studying and understanding rare family syndromes: from just one family, we may gain precious clues to why pancreatic cancer happens, how we may prevent it or catch it earlier, and how we may treat it more effectively," Dr. Nissim said.

Testing for this genetic mutation, especially in individuals with a strong family history of pancreatic cancer, may be warranted in the future. Also, additional studies may reveal insights on how well patients respond to different treatments based on whether their pancreatic cancer is associated with this or other inherited genetic mutations.

A powerful example of possible hereditary pancreatic cancer can be seen in the family of former US President Jimmy Carter, whose brother, father, and two sisters all died of pancreatic cancer. His mother died of breast cancer that metasized to the pancreas ( ( Jimmy Carter is now 94 years of age and never had pancreatic cancer. He did have malignant melanoma very recently and that has been “cured” by a novel new therapy. The major environmental difference President Carter notes between himself and his pancreatic cancer-afflicted family members is that they all smoked, while he never did. The definitive causative difference in President Carter’s different susceptibility to pancreatic cancer has not been established.

[Press release] [Nature Genetics abstract]