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Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nat Genet 2019 Sep;51(9):1308-1314

Date

08/14/2019

Pubmed ID

31406347

Pubmed Central ID

PMC7159804

DOI

10.1038/s41588-019-0475-y

Scopus ID

2-s2.0-85070822684 (requires institutional sign-in at Scopus site)   41 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.

Author List

Nissim 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 XX, Ukaegbu CI, Jennings BC, Paulo JA, Gableske S, Fierke CA, Getz G, Sunyaev SR, Wade Harper J, Cichowski K, Kimmelman AC, Houvras Y, Syngal S, Williams C, Goessling W

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Amino Acid Sequence
Animals
Carcinoma
Carcinoma, Pancreatic Ductal
Cell Proliferation
Female
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Male
Middle Aged
Pancreatic Neoplasms
Pedigree
Prenylation
Proto-Oncogene Proteins p21(ras)
Sequence Homology
Zebrafish
rab GTP-Binding Proteins