Publicação
Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs
| Resumo: | Aims: Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10-40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis. Methods and results: Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of 'cryptic'KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases. Conclusions: In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs. |
|---|---|
| Autores principais: | Martinho, Olga |
| Outros Autores: | Gouveia, António; Pereira, Marta Sofia Carvalho Ribeiro Viana; Silva, Paula; Pimenta, Amadeu; Reis, R. M.; Lopes, José Manuel |
| Assunto: | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| Ano: | 2009 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| _version_ | 1867439873877606400 |
|---|---|
| author | Martinho, Olga |
| author2 | Gouveia, António Pereira, Marta Sofia Carvalho Ribeiro Viana Silva, Paula Pimenta, Amadeu Reis, R. M. Lopes, José Manuel |
| author2_role | author author author author author author |
| author_facet | Martinho, Olga Gouveia, António Pereira, Marta Sofia Carvalho Ribeiro Viana Silva, Paula Pimenta, Amadeu Reis, R. M. Lopes, José Manuel |
| author_role | author |
| contributor_name_str_mv | RepositóriUM - Universidade do Minho |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Martinho, Olga\"},{\"Person.name\":\"Gouveia, António\"},{\"Person.name\":\"Pereira, Marta Sofia Carvalho Ribeiro Viana\"},{\"Person.name\":\"Silva, Paula\"},{\"Person.name\":\"Pimenta, Amadeu\"},{\"Person.name\":\"Reis, R. M.\"},{\"Person.name\":\"Lopes, José Manuel\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | RepositóriUM - Universidade do Minho |
| datacite.creators.creator.creatorName.fl_str_mv | Martinho, Olga Gouveia, António Pereira, Marta Sofia Carvalho Ribeiro Viana Silva, Paula Pimenta, Amadeu Reis, R. M. Lopes, José Manuel |
| datacite.date.Accepted.fl_str_mv | 2009-07-01T00:00:00Z |
| datacite.date.embargoed.fl_str_mv | 10000-01-01T00:00:00Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| datacite.subjects.subject.fl_str_mv | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| datacite.titles.title.fl_str_mv | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| dc.contributor.none.fl_str_mv | RepositóriUM - Universidade do Minho |
| dc.creator.none.fl_str_mv | Martinho, Olga Gouveia, António Pereira, Marta Sofia Carvalho Ribeiro Viana Silva, Paula Pimenta, Amadeu Reis, R. M. Lopes, José Manuel |
| dc.date.Accepted.fl_str_mv | 2009-07-01T00:00:00Z |
| dc.date.embargoed.fl_str_mv | 10000-01-01T00:00:00Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | https://hdl.handle.net/1822/67600 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | Blackwell Publishing |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| dc.subject.none.fl_str_mv | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| dc.title.fl_str_mv | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Aims: Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10-40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis. Methods and results: Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of 'cryptic'KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases. Conclusions: In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs. |
| dirty | 0 |
| eu_rights_str_mv | restrictedAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorium.uminho.pt/bitstreams/9a72f975-6eee-4013-88e9-b805f51b31c8/download |
| id | rum_a49eb03a76a45878e833ea09fe03abfc |
| identifier.url.fl_str_mv | https://hdl.handle.net/1822/67600 |
| instacron_str | repositorium |
| institution | Universidade do Minho |
| instname_str | Universidade do Minho |
| language | eng |
| network_acronym_str | rum |
| network_name_str | RepositóriUM - Universidade do Minho |
| oai_identifier_str | oai:repositorium.uminho.pt:1822/67600 |
| organization_str_mv | urn:organizationAcronym:repositorium |
| person_str_mv | Martinho, Olga Gouveia, António Pereira, Marta Sofia Carvalho Ribeiro Viana Silva, Paula Pimenta, Amadeu Reis, R. M. Lopes, José Manuel |
| publishDate | 2009 |
| publisher.none.fl_str_mv | Blackwell Publishing |
| reponame_str | RepositóriUM - Universidade do Minho |
| repository_id_str | urn:repositoryAcronym:rum |
| service_str_mv | urn:repositoryAcronym:rum |
| spelling | engBlackwell PublishingporAims: Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10-40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis. Methods and results: Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of 'cryptic'KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases. Conclusions: In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs.application/pdfporLow frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTsMartinho, OlgaGouveia, AntónioPereira, Marta Sofia Carvalho Ribeiro VianaSilva, PaulaPimenta, AmadeuReis, R. M.Lopes, José ManuelHostingInstitutionOrganizationalRepositóriUM - Universidade do Minhoe-mailmailto:repositorium@usdb.uminho.ptrepositorium@usdb.uminho.ptPMID19614767ISSNIsPartOf0309-0167EISSNIsPartOf1365-2559DOIIsPartOf10.1111/j.1365-2559.2009.03323.x2009-072009-07-01T00:00:00Z10000-01-01T00:00:00ZHandlehttps://hdl.handle.net/1822/67600http://purl.org/coar/access_right/c_16ecrestricted accessAdultAgedAged, 80 and overBiomarkers, TumorExtracellular Signal-Regulated MAP KinasesFemaleGastrointestinal NeoplasmsGastrointestinal Stromal TumorsHumansMaleMiddle AgedMitogen-Activated Protein Kinase KinasesMutationsPrognosisProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-kitProto-Oncogene Proteins p21(ras)Receptor, Platelet-Derived Growth Factor alphaRetrospective StudiesSignal TransductionActivationGISTsMAP kinaseWild-type706618 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_f1cfapplication/pdffulltexthttps://repositorium.uminho.pt/bitstreams/9a72f975-6eee-4013-88e9-b805f51b31c8/download |
| spellingShingle | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs Martinho, Olga Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| status | SINGLETON |
| subject.fl_str_mv | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| title | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| title_full | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| title_fullStr | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| title_full_unstemmed | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| title_short | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| title_sort | Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs |
| topic | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| topic_facet | Adult Aged Aged, 80 and over Biomarkers, Tumor Extracellular Signal-Regulated MAP Kinases Female Gastrointestinal Neoplasms Gastrointestinal Stromal Tumors Humans Male Middle Aged Mitogen-Activated Protein Kinase Kinases Mutations Prognosis Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-kit Proto-Oncogene Proteins p21(ras) Receptor, Platelet-Derived Growth Factor alpha Retrospective Studies Signal Transduction Activation GISTs MAP kinase Wild-type |
| url | https://hdl.handle.net/1822/67600 |
| visible | 1 |