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

Sahar Nissim, Ignaty Leshchiner, Joseph D. Mancias, Matthew B. Greenblatt, Ophélia Maertens, Christopher A. Cassa, Jill A. Rosenfeld, Andrew G. Cox, John Hedgepeth, Julia I. Wucherpfennig, Andrew J. Kim, Jake E. Henderson, Patrick Gonyo, Anthony Brandt, Ellen Lorimer, Bethany Unger, Jeremy W. Prokop, Jerry R. Heidel, Xiao Xu Wang, Chinedu I. UkaegbuBenjamin C. Jennings, Joao A. Paulo, Sebastian Gableske, Carol A. Fierke, Gad Getz, Shamil R. Sunyaev, J. Wade Harper, Karen Cichowski, Alec C. Kimmelman, Yariv Houvras, Sapna Syngal, Carol Williams, Wolfram Goessling

Research output: Contribution to journalLetterpeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1308-1314
Number of pages7
JournalNature Genetics
Volume51
Issue number9
DOIs
StatePublished - Sep 1 2019
Externally publishedYes

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