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

2019Journal article Open access
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dc.contributor.authorRamos De Matos, Mafalda
dc.contributor.authorPosa, Ioana
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorMorais, Vanessa A.
dc.contributor.authorGrosso, Ana Rita
dc.contributor.authorde Almeida, Sérgio F.
dc.date.accessioned2021-10-26T15:22:45Z
dc.date.available2021-10-26T15:22:45Z
dc.date.issued2019
dc.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/).pt_PT
dc.description.abstractIntratumor 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancers (Basel). 2019 Mar 20;11(3):391pt_PT
dc.identifier.doi10.3390/cancers11030391pt_PT
dc.identifier.eissn2072-6694
dc.identifier.urihttp://hdl.handle.net/10451/50022
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationPTDC/BIM-ONC/0016-2014pt_PT
dc.relationEMBO-IG-3309pt_PT
dc.relationERC-StG-679168pt_PT
dc.relationFCT/IF/01693/2014/CP1236/CT0003pt_PT
dc.relationLISBOA-01-0145-FEDER-016394pt_PT
dc.relationInstituto de Medicina Molecular
dc.relationNOVEL MECHANISMS OFGENOMIC AND EPIGENOMIC STABILITY
dc.relation.publisherversionhttps://www.mdpi.com/journal/cancerspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCancerpt_PT
dc.subjectEpigeneticspt_PT
dc.subjectGenomic instabilitypt_PT
dc.subjectIntratumor heterogeneitypt_PT
dc.subjectMitochondrial metabolismpt_PT
dc.titleA systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifierspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleInstituto de Medicina Molecular
oaire.awardTitleNOVEL MECHANISMS OFGENOMIC AND EPIGENOMIC STABILITY
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FBIA-MOL%2F30438%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F28660%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F50005%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F92208%2F2013/PT
oaire.citation.issue3pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume11pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameRamos de Matos
person.familyNameCarvalho
person.familyNameMorais
person.familyNameGrosso
person.familyNameFERNANDES DE ALMEIDA
person.givenNameMafalda
person.givenNameFilipa
person.givenNameVanessa
person.givenNameAna Rita
person.givenNameSÉRGIO ALEXANDRE
person.identifierI-6656-2013
person.identifier.ciencia-idA219-1813-5FFE
person.identifier.ciencia-id3D18-571E-133A
person.identifier.ciencia-id7D18-F40F-7CC1
person.identifier.orcid0000-0002-4206-2854
person.identifier.orcid0000-0002-0074-0741
person.identifier.orcid0000-0002-0830-0548
person.identifier.orcid0000-0001-6974-4209
person.identifier.orcid0000-0002-7774-1355
person.identifier.ridF-3215-2011
person.identifier.scopus-author-id26424235400
person.identifier.scopus-author-id26639262500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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