Researchers have determined that an inherited mutation in the RABL3 gene increases the risk of pancreatic cancer.
One of the most aggressive malignancies, pancreatic cancer has limited treatment options and a low survival rate. While approximately 10% of patients exhibit a hereditary pattern, with multiple cases in a single family, it was until now unclear which genes predispose individuals to developing pancreatic cancer.
Researchers led by first author Sahar Nissim, MD, PhD, a cancer geneticist, gastroenterologist, and Instructor of Medicine at the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, have identified an inherited mutation in the RABL3 gene as a risk factor for pancreatic cancer. Dr. Nissim and colleagues evaluated a family in which five members had been diagnosed with pancreatic cancer and multiple members had been diagnosed with other types of cancer. The researchers performed whole-genome sequencing analysis in the DNA of two of the family members with pancreatic cancer and identified the RABL3 mutation in both; the mutation was also found in the DNA of several other family members with cancer and one member who has not been diagnosed with cancer. Additionally, Dr. Nissim and colleagues recapitulated the RABL3 mutation in zebrafish models and found that populations carrying the mutation had significantly higher rates of pancreatic cancer.
The investigators determined that individuals are born with the RABL3 mutation and that it increases the risk of developing pancreatic cancer later in life. Their research could pave the way for individuals with a family history of pancreatic cancer to undergo genetic testing so that those who carry the mutation could undergo regular screening for pancreatic cancer, potentially enabling its detection at an earlier stage.
"This work highlights the power of studying and understanding rare family syndromes: from just one family, we have uncovered broadly important insights into pancreatic cancer and how we may better prevent or treat it," conclude Dr. Nissim and colleagues in their study, now published in Nature Genetics. "We anticipate that testing for this genetic mutation will be recommended [for] any individual with a strong family history of pancreatic cancer."
For More Information
Nissim S, Leshchiner I, Mancias J, et al (2019). Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer risk. Nat Genet. [Epub ahead of print] DOI:10.1038/s41588-019-0475-y
Image credit: Dr. Lance Liotta Laboratory