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

2010-02-15Artigo científico Acesso aberto
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dc.contributor.authorVelho, Sérgia
dc.contributor.authorOliveira, Carla
dc.contributor.authorParedes, Joana
dc.contributor.authorSousa, Sónia
dc.contributor.authorLeite, Marina
dc.contributor.authorMatos, Paulo
dc.contributor.authorMilanezi, Fernanda
dc.contributor.authorRibeiro, Ana Sofia
dc.contributor.authorMendes, Nuno
dc.contributor.authorLicastro, Danilo
dc.contributor.authorKarhu, Auli
dc.contributor.authorOliveira, Maria José
dc.contributor.authorLigtenberg, Marjolijn
dc.contributor.authorHamelin, Richard
dc.contributor.authorCarneiro, Fátima
dc.contributor.authorLindblom, Annika
dc.contributor.authorPeltomaki, Paivi
dc.contributor.authorCastedo, Sérgio
dc.contributor.authorSchwartz, Simó Jr
dc.contributor.authorJordan, Peter
dc.contributor.authorAaltonen, Lauri A.
dc.contributor.authorHofstra, Robert M.W.
dc.contributor.authorSuriano, Gianpaolo
dc.contributor.authorStupka, Elia
dc.contributor.authorFialho, Arsenio M
dc.contributor.authorSeruca, Raquel
dc.date.accessioned2011-09-15T11:29:59Z
dc.date.available2011-09-15T11:29:59Z
dc.date.issued2010-02-15
dc.description.abstractMixed 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.por
dc.identifier.citationHum Mol Genet. 2010 Feb 15;19(4):697-706. Epub 2009 Dec 2por
dc.identifier.issn0964-6906
dc.identifier.otherdoi:10.1093/hmg/ddp536
dc.identifier.urihttp://hdl.handle.net/10400.18/174
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherOxford University Presspor
dc.relation.publisherversionhttp://hmg.oxfordjournals.org/content/19/4/697.fullpor
dc.subjectVias de Transdução de Sinal e Patologias Associadaspor
dc.titleMixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.por
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage706por
oaire.citation.startPage697por
oaire.citation.titleHuman Molecular Geneticspor
rcaap.rightsopenAccesspor
rcaap.typearticlepor

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