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

18 Citations (Scopus)

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

Fingerprint

DNA Mismatch Repair
Mutation
Genes
Neoplasms
Missense Mutation
Phosphotransferases
Carcinoma
mitogen-activated protein kinase kinase kinase 11
Gastrointestinal Neoplasms
Protein-Serine-Threonine Kinases
Nude Mice
Colorectal Neoplasms
Phenotype
Cell Line

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Velho, S., Oliveira, C., Paredes, J., Sousa, S., Leite, M., Matos, P., ... 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

Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. / Velho, Sérgia; Oliveira, Carla; Paredes, Joana; Sousa, Sónia; Leite, Marina; Matos, Paulo; Milanezi, Fernanda; Ribeiro, Ana Sofia; Mendes, Nuno; Licastro, Danilo; Karhu, Auli; Oliveira, Maria José; Ligtenberg, Marjolijn; Hamelin, Richard; Carneiro, Fátima; Lindblom, Annika; Peltomaki, Paivi; Castedo, Sérgio; Schwartz, Simó; Jordan, Peter; Aaltonen, Lauri A.; Hofstra, Robert M W; Suriano, Gianpaolo; Stupka, Elia; Fialho, Arsenio M.; Seruca, Raquel.

In: Human Molecular Genetics, Vol. 19, No. 4, ddp536, 2010, p. 697-706.

Research output: Contribution to journalArticle

Velho, S, Oliveira, C, Paredes, J, Sousa, S, Leite, M, Matos, P, Milanezi, F, Ribeiro, AS, Mendes, N, Licastro, D, Karhu, A, Oliveira, MJ, Ligtenberg, M, Hamelin, R, Carneiro, F, Lindblom, A, Peltomaki, P, Castedo, S, Schwartz, S, Jordan, P, Aaltonen, LA, Hofstra, RMW, Suriano, G, Stupka, E, Fialho, AM & Seruca, R 2010, 'Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours', Human Molecular Genetics, vol. 19, no. 4, ddp536, pp. 697-706. https://doi.org/10.1093/hmg/ddp536
Velho, Sérgia ; Oliveira, Carla ; Paredes, Joana ; Sousa, Sónia ; Leite, Marina ; Matos, Paulo ; Milanezi, Fernanda ; Ribeiro, Ana Sofia ; Mendes, Nuno ; Licastro, Danilo ; Karhu, Auli ; Oliveira, Maria José ; Ligtenberg, Marjolijn ; Hamelin, Richard ; Carneiro, Fátima ; Lindblom, Annika ; Peltomaki, Paivi ; Castedo, Sérgio ; Schwartz, Simó ; Jordan, Peter ; Aaltonen, Lauri A. ; Hofstra, Robert M W ; Suriano, Gianpaolo ; Stupka, Elia ; Fialho, Arsenio M. ; Seruca, Raquel. / Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 4. pp. 697-706.
@article{a2281840e4bf4dd4bb6b765d15ed9c48,
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 tomismatch repair deficiency. Further,we demonstrated that MLK3 missense mutations found in MSI gastrointestinal carcinomas are functionally relevant.",
author = "S{\'e}rgia Velho and Carla Oliveira and Joana Paredes and S{\'o}nia Sousa and Marina Leite and Paulo Matos and Fernanda Milanezi and Ribeiro, {Ana Sofia} and Nuno Mendes and Danilo Licastro and Auli Karhu and Oliveira, {Maria Jos{\'e}} and Marjolijn Ligtenberg and Richard Hamelin and F{\'a}tima Carneiro and Annika Lindblom and Paivi Peltomaki and S{\'e}rgio Castedo and Sim{\'o} Schwartz and Peter Jordan and Aaltonen, {Lauri A.} and Hofstra, {Robert M W} and Gianpaolo Suriano and Elia Stupka and Fialho, {Arsenio M.} and Raquel Seruca",
year = "2010",
doi = "10.1093/hmg/ddp536",
language = "English",
volume = "19",
pages = "697--706",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "4",

}

TY - JOUR

T1 - Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours

AU - Velho, Sérgia

AU - Oliveira, Carla

AU - Paredes, Joana

AU - Sousa, Sónia

AU - Leite, Marina

AU - Matos, Paulo

AU - Milanezi, Fernanda

AU - Ribeiro, Ana Sofia

AU - Mendes, Nuno

AU - Licastro, Danilo

AU - Karhu, Auli

AU - Oliveira, Maria José

AU - Ligtenberg, Marjolijn

AU - Hamelin, Richard

AU - Carneiro, Fátima

AU - Lindblom, Annika

AU - Peltomaki, Paivi

AU - Castedo, Sérgio

AU - Schwartz, Simó

AU - Jordan, Peter

AU - Aaltonen, Lauri A.

AU - Hofstra, Robert M W

AU - Suriano, Gianpaolo

AU - Stupka, Elia

AU - Fialho, Arsenio M.

AU - Seruca, Raquel

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77950353937&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950353937&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp536

DO - 10.1093/hmg/ddp536

M3 - Article

C2 - 19955118

AN - SCOPUS:77950353937

VL - 19

SP - 697

EP - 706

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 4

M1 - ddp536

ER -