Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
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.
Velho
Sérgia
S
IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, 4200-465 Porto, Portugal.
Oliveira
Carla
C
Paredes
Joana
J
Sousa
Sónia
S
Leite
Marina
M
Matos
Paulo
P
Milanezi
Fernanda
F
Ribeiro
Ana Sofia
AS
Mendes
Nuno
N
Licastro
Danilo
D
Karhu
Auli
A
Oliveira
Maria José
MJ
Ligtenberg
Marjolijn
M
Hamelin
Richard
R
Carneiro
Fátima
F
Lindblom
Annika
A
Peltomaki
Paivi
P
Castedo
Sérgio
S
Schwartz
Simó
S
Jordan
Peter
P
Aaltonen
Lauri A
LA
Hofstra
Robert M W
RM
Suriano
Gianpaolo
G
Stupka
Elia
E
Fialho
Arsenio M
AM
Seruca
Raquel
R
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
D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11