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Nat Genet. 2019 Sep;51(9):1308-1314. doi: 10.1038/s41588-019-0475-y. Epub 2019 Aug 12.

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

Author information

1
Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Dana-Farber Cancer Institute, Boston, MA, USA.
4
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
5
The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
7
Department of Pathology and Laboratory Medicine and the Hospital for Special Surgery, Weill Cornell Medical College, Cornell University, New York, NY, USA.
8
The Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
9
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
10
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
11
Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
12
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
13
Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
14
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
15
Cancer Center and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
16
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
17
Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
18
Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA.
19
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. wgoessling@partners.org.
20
Dana-Farber Cancer Institute, Boston, MA, USA. wgoessling@partners.org.
21
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA. wgoessling@partners.org.
22
The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA. wgoessling@partners.org.
23
Harvard Stem Cell Institute, Cambridge, MA, USA. wgoessling@partners.org.
24
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. wgoessling@partners.org.

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.

PMID:
31406347
DOI:
10.1038/s41588-019-0475-y

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