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

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 ad...

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Published inNature genetics Vol. 51; no. 9; pp. 1308 - 1314
Main Authors Nissim, Sahar, Leshchiner, Ignaty, Mancias, Joseph D, Greenblatt, Matthew B, Maertens, Ophélia, Cassa, Christopher A, Rosenfeld, Jill A, Cox, Andrew G, Hedgepeth, John, Wucherpfennig, Julia I, Kim, Andrew J, Henderson, Jake E, Gonyo, Patrick, Brandt, Anthony, Lorimer, Ellen, Unger, Bethany, Prokop, Jeremy W, Heidel, Jerry R, Wang, Xiao-Xu, Ukaegbu, Chinedu I, Jennings, Benjamin C, Paulo, Joao A, Gableske, Sebastian, Fierke, Carol A, Getz, Gad, Sunyaev, Shamil R, Wade Harper, J, Cichowski, Karen, Kimmelman, Alec C, Houvras, Yariv, Syngal, Sapna, Williams, Carol, Goessling, Wolfram
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.09.2019
Subjects
Adenocarcinoma
Adult
Aged
Aged, 80 and over
Amino Acid Sequence
Animals
Cancer
Carcinoma - genetics
Carcinoma - metabolism
Carcinoma - pathology
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Care and treatment
Cell growth
Cell Proliferation
Developmental disabilities
DNA sequencing
Female
Genes
Genetic aspects
Genetic Predisposition to Disease
Genetic screening
Genomes
Germ-Line Mutation
Humans
K-Ras protein
Male
Mass spectrometry
Mass spectroscopy
Middle Aged
Mutation
Nucleotide sequence
Nucleotide sequencing
Pancreatic cancer
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Pedigree
Prenylation
Proteins
Proteomics
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
rab GTP-Binding Proteins - genetics
Scientific imaging
Sequence Homology
Siblings
Tumors
Zebra fish
Zebrafish
United States > US
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Summary: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.
Bibliography:S.N. and W.G. conceived and designed the overall project. S.S. and C.I.U. assisted with selecting the family, gathering the clinical histories and collecting DNA samples under human subject IRB-approved protocols. S.N., W.G. and I.L. designed the WGS analysis. I.L. performed the WGS analysis and candidate variant filtering. S.N., J.W., A.J.K., J.E.H., A.G.C. and J.H. designed and generated the zebrafish rabl3 mutant lines and performed the cancer studies. J.R.H. and S.N. performed zebrafish histology preparation and analysis. J.D.M. performed and analyzed the AP–MS experiments and CompPASS suite protein interactomics. S.N., W.G. and C.W. conceived and designed the in vitro immunoprecipitation, prenylation assays and HEK293T cell proliferation assays, and P.G., A.B., E.L. and B.U. performed these experiments. S.N. and O.M. designed and performed RASless MEF experiments. J.W.P. performed protein structural modeling. B.C.J. and C.A.F. designed and performed purification of recombinant protein. J.A.P., S.G. and J.D.M. assisted with mass spectrometry analysis. Y.H. assisted with RNA-seq data analysis. M.B.G. performed the zebrafish μCT and bone histomorphometric analysis. O.M., X.W. and J.D.M. provided assistance with tissue culture experiments. C.A.C. and J.A.R. provided analysis of clinical exome sequencing data. C.A.C. and I.L. provided analysis of variants in the Exome Aggregation Consortium. J.W.H., G.G., S.R.S., K.C. and A.C.K. provided overall input. S.N. and W.G. wrote the manuscript. All authors reviewed and edited the manuscript.
Author contributions
ISSN:1061-4036
1546-1718
DOI:10.1038/s41588-019-0475-y