PUBLICATION
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer
- Authors
- Nissim, S., Leshchiner, I., Mancias, J.D., Greenblatt, M.B., Maertens, O., Cassa, C.A., Rosenfeld, J.A., Cox, A.G., Hedgepeth, J., Wucherpfennig, J.I., Kim, A.J., Henderson, J.E., Gonyo, P., Brandt, A., Lorimer, E., Unger, B., Prokop, J.W., Heidel, J.R., Wang, X.X., Ukaegbu, C.I., Jennings, B.C., Paulo, J.A., Gableske, S., Fierke, C.A., Getz, G., Sunyaev, S.R., Wade Harper, J., Cichowski, K., Kimmelman, A.C., Houvras, Y., Syngal, S., Williams, C., Goessling, W.
- ID
- ZDB-PUB-190814-13
- Date
- 2019
- Source
- Nature Genetics 51(9): 1308-1314 (Journal)
- Registered Authors
- Nissim, Sahar
- Keywords
- none
- Datasets
- GEO:GSE129081
- MeSH Terms
-
- Aged
- Cell Proliferation
- Zebrafish
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology*
- Humans
- rab GTP-Binding Proteins/genetics*
- Amino Acid Sequence
- Genetic Predisposition to Disease*
- Male
- Germ-Line Mutation*
- Carcinoma/genetics
- Carcinoma/metabolism
- Carcinoma/pathology*
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology*
- Sequence Homology
- Aged, 80 and over
- Pedigree
- Proto-Oncogene Proteins p21(ras)/genetics
- Proto-Oncogene Proteins p21(ras)/metabolism*
- Middle Aged
- Prenylation*
- Female
- Adult
- Animals
- PubMed
- 31406347 Full text @ Nat. Genet.
Citation
Nissim, S., Leshchiner, I., Mancias, J.D., Greenblatt, M.B., Maertens, O., Cassa, C.A., Rosenfeld, J.A., Cox, A.G., Hedgepeth, J., Wucherpfennig, J.I., Kim, A.J., Henderson, J.E., Gonyo, P., Brandt, A., Lorimer, E., Unger, B., Prokop, J.W., Heidel, J.R., Wang, X.X., Ukaegbu, C.I., Jennings, B.C., Paulo, J.A., Gableske, S., Fierke, C.A., Getz, G., Sunyaev, S.R., Wade Harper, J., Cichowski, K., Kimmelman, A.C., Houvras, Y., Syngal, S., Williams, C., Goessling, W. (2019) Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nature Genetics. 51(9):1308-1314.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping