title: Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
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 to mismatch repair deficiency. Further, we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.
authors: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.
authors: Sérgia
authors: S
authors: Velho
authors: Carla
authors: C
authors: Oliveira
authors: Joana
authors: J
authors: Paredes
authors: Sónia
authors: S
authors: Sousa
authors: Marina
authors: M
authors: Leite
authors: Paulo
authors: P
authors: Matos
authors: Fernanda
authors: F
authors: Milanezi
authors: Ana Sofia
authors: AS
authors: Ribeiro
authors: Nuno
authors: N
authors: Mendes
authors: Danilo
authors: D
authors: Licastro
authors: Auli
authors: A
authors: Karhu
authors: Maria José
authors: MJ
authors: Oliveira
authors: Marjolijn
authors: M
authors: Ligtenberg
authors: Richard
authors: R
authors: Hamelin
authors: Fátima
authors: F
authors: Carneiro
authors: Annika
authors: A
authors: Lindblom
authors: Paivi
authors: P
authors: Peltomaki
authors: Sérgio
authors: S
authors: Castedo
authors: Simó
authors: S
authors: Schwartz
authors: Peter
authors: P
authors: Jordan
authors: Lauri A
authors: LA
authors: Aaltonen
authors: Robert M W
authors: RM
authors: Hofstra
authors: Gianpaolo
authors: G
authors: Suriano
authors: Elia
authors: E
authors: Stupka
authors: Arsenio M
authors: AM
authors: Fialho
authors: Raquel
authors: R
authors: Seruca
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair; D005770:Gastrointestinal Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11