Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options1. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families2. We perform 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. Heterozygous rabl3 mutant zebrafish show increased susceptibility to cancer formation. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases3. Indeed, 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. Our studies identify RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer.
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This work was supported by the NIH grant nos. K08 DK105326 (to S.N.); R01 DK090311, R01 DK095721 and R24 OD017870 (to W.G.); R01 GM095567, R01 CA157490, R01 CA188048, P01 CA117969 and R35 CA232124 (to A.C.K.); R01 CA188871 (to C.W.) and R01 GM040602 (to C.A.F.); as well as grants from the National Pancreas Foundation (to S.N.), the Harvard Digestive Diseases Center (grant no. P30 DK034854 to S.N. and W.G.), the Ken and Louise Goldberg Award (to S.N.), an ACS Research Scholar Grant (RSG-13-298-01-TBG to A.C.K.), the Lustgarten Foundation and SU2C (to A.C.K) and the Anna Fuller Fund and the Claudia Adams Barr Program for Innovative Cancer Research (to W.G.). S.N. is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. W.G. is a Pew Scholar in the Biomedical Sciences.
A.C.K. has financial interests in Vescor Therapeutics, LLC. A.C.K. is an inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach and the autophagic control of iron metabolism. A.C.K. is on the SAB of Cornerstone/Rafael Pharmaceuticals. G.G. receives research funds from IBM and Pharmacyclics. W.G. receives patent royalties from FATE Therapeutics and is on the SAB of Camp4 Therapeutics.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Nissim, S., Leshchiner, I., Mancias, J.D. et al. Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat Genet 51, 1308–1314 (2019). https://doi.org/10.1038/s41588-019-0475-y
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