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Nat Genet DOI:10.1038/s41588-019-0475-y

Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.

Publication TypeJournal Article
Year of Publication2019
AuthorsNissim, S, Leshchiner, I, Mancias, JD, Greenblatt, MB, Maertens, O, Cassa, CA, Rosenfeld, JA, Cox, AG, Hedgepeth, J, Wucherpfennig, JI, Kim, AJ, Henderson, JE, Gonyo, P, Brandt, A, Lorimer, E, Unger, B, Prokop, JW, Heidel, JR, Wang, X-X, Ukaegbu, CI, Jennings, BC, Paulo, JA, Gableske, S, Fierke, CA, Getz, G, Sunyaev, SR, J Harper, W, Cichowski, K, Kimmelman, AC, Houvras, Y, Syngal, S, Williams, C, Goessling, W
JournalNat Genet
Date Published2019 Sep

Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families. 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 GTPases. 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.


Alternate JournalNat. Genet.
PubMed ID31406347
Grant ListK08 DK105326 / DK / NIDDK NIH HHS / United States