A Previously Unknown Mutation in RABL3 Is Linked to Hereditary PDAC

Approximately 10% of cases of pancreatic ductal adenocarcinoma (PDAC) occur in people with a family history of the condition, but few causative mutations have been identified. Using whole-genome sequencing, Nissim and colleagues identified a rare nonsense mutation in RABL3, a gene about which little is known, in a family with a history of cancers, particularly PDAC. As would be expected of an oncogene, expression of the mutant RABL3 in a human cell line led to increased proliferation. Providing evidence for the role of the RABL3 mutation in cancer pathogenesis, zebrafish heterozygous for a truncated Rabl3 developed cancers at an accelerated rate after treatment with chemical carcinogens or on a Trp53-null background. Affinity purification-mass spectrometry using mutant and wild-type (WT) RABL3 uncovered several high-confidence interacting proteins, including Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1, also known as SmgGDS), a chaperone protein suspected to bind and prenylate small GTPases. Protein prenylation—the chemical linkage of hydrophobic molecules such as lipids to proteins—is required for the function of some proteins, including KRAS, and abnormal KRAS signaling is prevalent in PDAC. The mutant RABL3 increased the rate of prenylation of both WT KRAS-4B and an oncogenic mutant KRAS-4B, and a mouse cell line with all Kras alleles excised did not exhibit increased proliferation caused by the RABL3 mutation, implying that mutant RABL3's oncogenic effects may be KRAS-dependent. Further implicating the RAS pathway in the pathology caused by the RABL3 mutation, zebrafish homozygous for a truncated Rabl3 had a phenotype resembling that of some human RASopathies, including stunted growth, marked spinal deformities, dysmorphia of the craniofacial and rib bones with impaired bone mineralization, and signs of motor or neurologic abnormalities. Collectively, these results indicate that a germline mutation in RABL3 not previously known to be associated with cancer is robustly associated with cancer development, indicating that investigation of other mutations in this gene may be of interest. Further, the connection between RABL3 and the RAS pathway may also be worth studying.

Nissim S, Leshchiner I, Mancias JD, Greenblatt MB, Maertens O, Cassa CA, et al. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat Genet 2019 Aug 12 [Epub ahead of print].

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