The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade glioma
Autor(a) principal: | |
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Data de Publicação: | 2014 |
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/1822/29193 |
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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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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The prognostic role of intragenic copy number breakpoints and identification of novel fusion genes in paediatric high grade gliomaFusionPaediatricGlioblastomaCopy numberIntragenicScience & TechnologyBACKGROUND: 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.We are grateful for support from the Rosetrees Trust, the Brain Tumour Charity and Fundacao para a Ciencia e Tecnologia, Portugal (PhD Studentship SFRH/BD/33473/2008). DC, AM, LB and CJ acknowledge NHS funding to the Biomedical Research Centre.BioMed Central (BMC)Universidade do MinhoCarvalho, DianaMackay, AlanBjerke, LynnGrundy, Richard G.Lopes, CelesteReis, R. M.Jones, Chris20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/29193eng2051-596010.1186/2051-5960-2-2324548782http://www.actaneurocomms.org/content/2/1/23info: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:RCAAP2023-07-21T12:53:50Zoai:repositorium.sdum.uminho.pt:1822/29193Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:53:19.716852Repositório 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 Science & Technology |
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, R. M. Jones, Chris |
author_role |
author |
author2 |
Mackay, Alan Bjerke, Lynn Grundy, Richard G. Lopes, Celeste Reis, R. M. Jones, Chris |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Carvalho, Diana Mackay, Alan Bjerke, Lynn Grundy, Richard G. Lopes, Celeste Reis, R. M. Jones, Chris |
dc.subject.por.fl_str_mv |
Fusion Paediatric Glioblastoma Copy number Intragenic Science & Technology |
topic |
Fusion Paediatric Glioblastoma Copy number Intragenic Science & Technology |
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 2014-01-01T00:00:00Z |
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/1822/29193 |
url |
http://hdl.handle.net/1822/29193 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2051-5960 10.1186/2051-5960-2-23 24548782 http://www.actaneurocomms.org/content/2/1/23 |
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 |
BioMed Central (BMC) |
publisher.none.fl_str_mv |
BioMed Central (BMC) |
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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1799133129307324416 |