The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma

Detalhes bibliográficos
Autor(a) principal: Carvalho, Diana
Data de Publicação: 2014
Outros Autores: Mackay, Alan, Bjerke, Lynn, Grundy, Richard G., Lopes, Celeste, Reis, Rui M., Jones, Chris
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/109353
https://doi.org/10.1186/2051-5960-2-23
Resumo: Background: Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints. Results: We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG – CSGALNACT2:RET and the complex fusion DHX57:TMEM178: MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG. Conclusions: These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.
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spelling The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade gliomaFusionPaediatricGlioblastomaCopy numberIntragenicAlgorithmsBrain NeoplasmsChildChild, PreschoolFemaleGene DeletionGene Expression ProfilingGliomaHumansInfantMaleN-AcetylgalactosaminyltransferasesOligonucleotide Array Sequence AnalysisOncogene Proteins, FusionRNA, Small InterferingChromosome BreakageDNA Copy Number VariationsBackground: Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints. Results: We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG – CSGALNACT2:RET and the complex fusion DHX57:TMEM178: MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG. Conclusions: These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.Springer Nature2014-02-18info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/109353http://hdl.handle.net/10316/109353https://doi.org/10.1186/2051-5960-2-23eng2051-5960Carvalho, DianaMackay, AlanBjerke, LynnGrundy, Richard G.Lopes, CelesteReis, Rui M.Jones, Chrisinfo: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:RCAAP2023-10-11T08:11:52Zoai:estudogeral.uc.pt:10316/109353Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:25:33.316655Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
title The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
spellingShingle The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
Carvalho, Diana
Fusion
Paediatric
Glioblastoma
Copy number
Intragenic
Algorithms
Brain Neoplasms
Child
Child, Preschool
Female
Gene Deletion
Gene Expression Profiling
Glioma
Humans
Infant
Male
N-Acetylgalactosaminyltransferases
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion
RNA, Small Interfering
Chromosome Breakage
DNA Copy Number Variations
title_short The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
title_full The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
title_fullStr The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
title_full_unstemmed The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
title_sort The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
author Carvalho, Diana
author_facet Carvalho, Diana
Mackay, Alan
Bjerke, Lynn
Grundy, Richard G.
Lopes, Celeste
Reis, Rui M.
Jones, Chris
author_role author
author2 Mackay, Alan
Bjerke, Lynn
Grundy, Richard G.
Lopes, Celeste
Reis, Rui M.
Jones, Chris
author2_role author
author
author
author
author
author
dc.contributor.author.fl_str_mv Carvalho, Diana
Mackay, Alan
Bjerke, Lynn
Grundy, Richard G.
Lopes, Celeste
Reis, Rui M.
Jones, Chris
dc.subject.por.fl_str_mv Fusion
Paediatric
Glioblastoma
Copy number
Intragenic
Algorithms
Brain Neoplasms
Child
Child, Preschool
Female
Gene Deletion
Gene Expression Profiling
Glioma
Humans
Infant
Male
N-Acetylgalactosaminyltransferases
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion
RNA, Small Interfering
Chromosome Breakage
DNA Copy Number Variations
topic Fusion
Paediatric
Glioblastoma
Copy number
Intragenic
Algorithms
Brain Neoplasms
Child
Child, Preschool
Female
Gene Deletion
Gene Expression Profiling
Glioma
Humans
Infant
Male
N-Acetylgalactosaminyltransferases
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion
RNA, Small Interfering
Chromosome Breakage
DNA Copy Number Variations
description Background: Paediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints. Results: We report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG – CSGALNACT2:RET and the complex fusion DHX57:TMEM178: MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG. Conclusions: These data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.
publishDate 2014
dc.date.none.fl_str_mv 2014-02-18
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/10316/109353
http://hdl.handle.net/10316/109353
https://doi.org/10.1186/2051-5960-2-23
url http://hdl.handle.net/10316/109353
https://doi.org/10.1186/2051-5960-2-23
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2051-5960
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
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
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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