{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nissim S"],"funding":["NIDDK NIH HHS","NHGRI NIH HHS","NCI NIH HHS","NIGMS NIH HHS","NIH HHS"],"pagination":["1308-1314"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7159804"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["51(9)"],"pubmed_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."],"journal":["Nature genetics"],"pubmed_title":["Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer."],"pmcid":["PMC7159804"],"funding_grant_id":["R01 GM095567","R01 GM132129","R03 DK122232","R01 CA157490","R01 DK090311","R01 GM040602","R01 HG010372","R01 DK095721","R24 OD017870","P30 DK034854","R01 CA188871","R35 CA232124","R01 CA188048","K08 DK105326","P01 CA117969"],"pubmed_authors":["Heidel JR","Hedgepeth J","Rosenfeld JA","Getz G","Leshchiner I","Prokop JW","Williams C","Mancias JD","Kim AJ","Sunyaev SR","Maertens O","Fierke CA","Paulo JA","Brandt A","Unger B","Wang XX","Nissim S","Wucherpfennig JI","Cichowski K","Greenblatt MB","Ukaegbu CI","Wade Harper J","Gonyo P","Henderson JE","Kimmelman AC","Cassa CA","Lorimer E","Jennings BC","Goessling W","Syngal S","Cox AG","Gableske S","Houvras Y"],"additional_accession":[]},"is_claimable":false,"name":"Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.","description":"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.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Sep","modification":"2020-11-19T10:09:47Z","creation":"2020-10-29T12:02:20Z"},"accession":"S-EPMC7159804","cross_references":{"pubmed":["31406347"],"doi":["10.1038/s41588-019-0475-y"]}}