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

Sérgia Velho, Carla Oliveira, Joana Paredes, Sónia Sousa, Marina Leite, Paulo Matos, Fernanda Milanezi, Ana Sofia Ribeiro, Nuno Mendes, Danilo Licastro, Auli Karhu, Maria José Oliveira, Marjolijn Ligtenberg, Richard Hamelin, Fátima Carneiro, Annika Lindblom, Paivi Peltomaki, Sérgio Castedo, Simó Schwartz, Peter JordanLauri A. Aaltonen, Robert M W Hofstra, Gianpaolo Suriano, Elia Stupka, Arsenio M. Fialho, Raquel Seruca

Research output: Contribution to journalArticle

Abstract

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 tomismatch repair deficiency. Further,we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.

Original languageEnglish
Article numberddp536
Pages (from-to)697-706
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number4
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Velho, S., Oliveira, C., Paredes, J., Sousa, S., Leite, M., Matos, P., Milanezi, F., Ribeiro, A. S., Mendes, N., Licastro, D., Karhu, A., Oliveira, M. J., Ligtenberg, M., Hamelin, R., Carneiro, F., Lindblom, A., Peltomaki, P., Castedo, S., Schwartz, S., ... Seruca, R. (2010). Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. Human Molecular Genetics, 19(4), 697-706. [ddp536]. https://doi.org/10.1093/hmg/ddp536