Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours

• Tipo: Artigo em Revista Científica Internacional
• Data: 2010

Autores

Velho S (Autor) FMUP; Oliveira C (Autor) FMUP; Carneiro F (Autor) FMUP; Sérgio Castedo (Autor) FMUP

Revista

Título: Human Molecular Genetics

Vol. 19

Páginas: 697-706

ISSN: 0964-6906

Editora: Oxford University Press

Indexação

ISI Web of Knowledge - 23 Citações

Scopus - 23 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Outras ciências médicas

Outras Informações

ID Authenticus: P-003-947

DOI: 10.1093/hmg/ddp536

Abstract (EN): Mixed lineage kinase 3 (MLK3) is a serine/threonine kinase, regulating MAPkinase signalling, in which cancer-associated mutations have never been reported. In this study, 174 primary gastrointestinal cancers (48 hereditary and 126 sporadic forms) and 7 colorectal cancer cell lines were screened for MLK3 mutations. MLK3 mutations were significantly associated with MSI phenotype in primary tumours (P = 0.0005), occurring in 21% of the MSI carcinomas. Most MLK3 somatic mutations identified were of the missense type (62.5%) and more than 80% of them affected evolutionarily conserved residues. A predictive 3D model points to the functional relevance of MLK3 missense mutations, which cluster in the kinase domain. Further, the model shows that most of the altered residues in the kinase domain probably affect MLK3 scaffold properties, instead of its kinase activity. MLK3 missense mutations showed transforming capacity in vitro and cells expressing the mutant gene were able to develop locally invasive tumours, when subcutaneously injected in nude mice. Interestingly, in primary tumours, MLK3 mutations occurred in KRAS and/or BRAF wild-type carcinomas, although not being mutually exclusive genetic events. In conclusion, we have demonstrated for the first time the presence of MLK3 mutations in cancer and its association to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 10