Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/174 |
Resumo: | 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. |
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Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours.Vias de Transdução de Sinal e Patologias AssociadasMixed 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.Oxford University PressRepositório Científico do Instituto Nacional de SaúdeVelho, SérgiaOliveira, CarlaParedes, JoanaSousa, SóniaLeite, MarinaMatos, PauloMilanezi, FernandaRibeiro, Ana SofiaMendes, NunoLicastro, DaniloKarhu, AuliOliveira, Maria JoséLigtenberg, MarjolijnHamelin, RichardCarneiro, FátimaLindblom, AnnikaPeltomaki, PaiviCastedo, SérgioSchwartz, Simó JrJordan, PeterAaltonen, Lauri A.Hofstra, Robert M.W.Suriano, GianpaoloStupka, EliaFialho, Arsenio MSeruca, Raquel2011-09-15T11:29:59Z2010-02-152010-02-15T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/174engHum Mol Genet. 2010 Feb 15;19(4):697-706. Epub 2009 Dec 20964-6906doi:10.1093/hmg/ddp536info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:38:03ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
title |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
spellingShingle |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. Velho, Sérgia Vias de Transdução de Sinal e Patologias Associadas |
title_short |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
title_full |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
title_fullStr |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
title_full_unstemmed |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
title_sort |
Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. |
author |
Velho, Sérgia |
author_facet |
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 Jr Jordan, Peter Aaltonen, Lauri A. Hofstra, Robert M.W. Suriano, Gianpaolo Stupka, Elia Fialho, Arsenio M Seruca, Raquel |
author_role |
author |
author2 |
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 Jr Jordan, Peter Aaltonen, Lauri A. Hofstra, Robert M.W. Suriano, Gianpaolo Stupka, Elia Fialho, Arsenio M Seruca, Raquel |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
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 Jr Jordan, Peter Aaltonen, Lauri A. Hofstra, Robert M.W. Suriano, Gianpaolo Stupka, Elia Fialho, Arsenio M Seruca, Raquel |
dc.subject.por.fl_str_mv |
Vias de Transdução de Sinal e Patologias Associadas |
topic |
Vias de Transdução de Sinal e Patologias Associadas |
description |
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. |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-02-15 2010-02-15T00:00:00Z 2011-09-15T11:29:59Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/174 |
url |
http://hdl.handle.net/10400.18/174 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Hum Mol Genet. 2010 Feb 15;19(4):697-706. Epub 2009 Dec 2 0964-6906 doi:10.1093/hmg/ddp536 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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1777303616108888064 |