A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers

Detalhes bibliográficos
Autor(a) principal: Ramos De Matos, Mafalda
Data de Publicação: 2019
Outros Autores: Posa, Ioana, Carvalho, Filipa, Morais, Vanessa A., Grosso, Ana Rita, de Almeida, Sérgio F.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/50022
Resumo: © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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spelling A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiersCancerEpigeneticsGenomic instabilityIntratumor heterogeneityMitochondrial metabolism© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance. It results from the continuous evolution of different clones of a tumor over time. However, the molecular features underlying the emergence of genetically-distinct subclonal cell populations remain elusive. Here, we conducted an exhaustive characterization of ITH across 2807 tumor samples from 16 cancer types. Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels. In particular, genes that regulate genome-wide histone and DNA methylation emerged as being determinant of high ITH. Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations. The ITH scores observed in knockout cells recapitulated the heterogeneity levels observed in patient tumor samples and correlated with a better mitochondrial bioenergetic performance under stress conditions. Our work provides new insights into tumor development, and discloses new drivers of ITH, which may be useful as either predictive biomarkers or therapeutic targets to improve cancer treatment.This research was funded by: PTDC/BIM-ONC/0016-2014 and PTDC/BIA-MOL/30438/2017 to S.F.d.A., PTDC/MED-ONC/28660/2017 to A.R.G, EMBO-IG-3309, ERC-StG-679168 and FCT/IF/01693/2014/CP1236/CT0003 to V.A.M.; LISBOA-01-0145-FEDER-016394 project co-funded by FEDER, through POR Lisboa, Portugal 2020-Programa Operacional Regional de Lisboa, PORTUGAL 2020 and Fundação para a Ciência e Tecnologia (FCT); UID/BIM/50005/2019 through Fundação para a Ciência e Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES)-Fundos do Orçamento de Estado; the iMM-Laço Fund. A.R.G. is the recipient of an FCT Investigator grant (IF/00510/2014). M.R.d.M. is recipient of a PhD fellowship: SFRH/BD/92208/2013. F.S.C. is the recipient of the fellowship iMM/BPD/122-2016.MDPIRepositório da Universidade de LisboaRamos De Matos, MafaldaPosa, IoanaCarvalho, FilipaMorais, Vanessa A.Grosso, Ana Ritade Almeida, Sérgio F.2021-10-26T15:22:45Z20192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/50022engCancers (Basel). 2019 Mar 20;11(3):39110.3390/cancers110303912072-6694info: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:RCAAP2023-11-08T16:54:02Zoai:repositorio.ul.pt:10451/50022Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:32.644345Repositório 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 A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
title A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
spellingShingle A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
Ramos De Matos, Mafalda
Cancer
Epigenetics
Genomic instability
Intratumor heterogeneity
Mitochondrial metabolism
title_short A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
title_full A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
title_fullStr A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
title_full_unstemmed A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
title_sort A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers
author Ramos De Matos, Mafalda
author_facet Ramos De Matos, Mafalda
Posa, Ioana
Carvalho, Filipa
Morais, Vanessa A.
Grosso, Ana Rita
de Almeida, Sérgio F.
author_role author
author2 Posa, Ioana
Carvalho, Filipa
Morais, Vanessa A.
Grosso, Ana Rita
de Almeida, Sérgio F.
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Ramos De Matos, Mafalda
Posa, Ioana
Carvalho, Filipa
Morais, Vanessa A.
Grosso, Ana Rita
de Almeida, Sérgio F.
dc.subject.por.fl_str_mv Cancer
Epigenetics
Genomic instability
Intratumor heterogeneity
Mitochondrial metabolism
topic Cancer
Epigenetics
Genomic instability
Intratumor heterogeneity
Mitochondrial metabolism
description © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-01-01T00:00:00Z
2021-10-26T15:22:45Z
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/10451/50022
url http://hdl.handle.net/10451/50022
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cancers (Basel). 2019 Mar 20;11(3):391
10.3390/cancers11030391
2072-6694
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 MDPI
publisher.none.fl_str_mv MDPI
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
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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
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