Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
Nat Genet
; 51(9): 1308-1314, 2019 09.
Article
em En
| MEDLINE
| ID: mdl-31406347
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Carcinoma
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Proteínas Proto-Oncogênicas p21(ras)
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Mutação em Linhagem Germinativa
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Predisposição Genética para Doença
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Proteínas rab de Ligação ao GTP
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Carcinoma Ductal Pancreático
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Prenilação
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
/
Aged
/
Aged80
/
Animals
/
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Nat Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos