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

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.

SUBMITTER: Nissim S

PROVIDER: S-EPMC7159804 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Nissim Sahar S Leshchiner Ignaty I Mancias Joseph D JD Greenblatt Matthew B MB Maertens Ophélia O Cassa Christopher A CA Rosenfeld Jill A JA Cox Andrew G AG Hedgepeth John J Wucherpfennig Julia I JI Kim Andrew J AJ Henderson Jake E JE Gonyo Patrick P Brandt Anthony A Lorimer Ellen E Unger Bethany B Prokop Jeremy W JW Heidel Jerry R JR Wang Xiao-Xu XX Ukaegbu Chinedu I CI Jennings Benjamin C BC Paulo Joao A JA Gableske Sebastian S Fierke Carol A CA Getz Gad G Sunyaev Shamil R SR Wade Harper J J Cichowski Karen K Kimmelman Alec C AC Houvras Yariv Y Syngal Sapna S Williams Carol C Goessling Wolfram W

Nature genetics 20190812 9

Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options<sup>1</sup>. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families<sup>2</sup>. 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 suscepti ...[more]

PMID: 31406347

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer.

Dataset Information

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

Publications

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

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