Mutations Linked to Familial Pancreatic Cancer Identified

Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families.

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.

A team of scientists working with the Massachusetts General Hospital (Boston, MA, USA) performed whole-genome sequence analysis in a family with multiple cases of pancreatic ductal adenocarcinoma and identify a germline truncating mutation in the member of the RAS oncogene family-like 3 (RABL3) gene. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases.

The truncated mutant RABL3 protein accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Finally, evidence in patient cohorts with developmental disorders implicates germline RABL3 mutations in RASopathy syndromes. The studies identified RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer.

Sahar Nissim, MD, PhD, a cancer geneticist and gastroenterologist and lead author of the study, said, “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.” The study was published on August 12, 2019, in the journal Nature Genetics.

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