A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorLABGAA, Ismail
dc.contributor.authorVILLACORTA-MARTIN, Carlos
dc.contributor.authorD'AVOLA, Delia
dc.contributor.authorCRAIG, Amanda J.
dc.contributor.authorFELDEN, Johann von
dc.contributor.authorMARTINS-FILHO, Sebastiao N.
dc.contributor.authorSIA, Daniela
dc.contributor.authorSTUECK, Ashley
dc.contributor.authorWARD, Stephen C.
dc.contributor.authorFIEL, M. Isabel
dc.contributor.authorMAHAJAN, Milind
dc.contributor.authorTABRIZIAN, Parissa
dc.contributor.authorTHUNG, Swan N.
dc.contributor.authorANG, Celina
dc.contributor.authorFRIEDMAN, Scott L.
dc.contributor.authorLLOVET, Josep M.
dc.contributor.authorSCHWARTZ, Myron
dc.contributor.authorVILLANUEVA, Augusto
dc.date.accessioned2018-09-13T15:26:52Z
dc.date.available2018-09-13T15:26:52Z
dc.date.issued2018
dc.description.abstractCellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500x coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.
dc.description.indexMEDLINE
dc.description.sponsorshipSwiss National Science Foundation
dc.description.sponsorshipFoundation Roberto Gianna Gonella
dc.description.sponsorshipFoundation SICPA
dc.description.sponsorshipGrant for Studies Broadening from the Spanish Association for the Study of the Liver (Asociacion Espanola para el Estudio del Higado, AEEH)
dc.description.sponsorshipCancer Research Grant from Nuovo Soldati Foundation
dc.description.sponsorshipRuth L. Kirschstein NRSA Institutional Research Training Grant [T32 CA078207]
dc.description.sponsorshipGerman Research Foundation [FE 1746/1-1]
dc.description.sponsorshipBrazilian National Council for Scientific and Technological Development
dc.description.sponsorshipAssociacao Piauiense de Combate ao Cancer
dc.description.sponsorshipEuropean Commission [259744, 667273-2]
dc.description.sponsorshipSamuel Waxman Cancer Research Foundation
dc.description.sponsorshipSpanish National Health Institute [SAF-2016-76390]
dc.description.sponsorshipAsociacion Espanola para el Estudio del Cancer [CA150272P1]
dc.description.sponsorshipU.S. Department of Defense [CA150272P1, CA150272P3, W81XWH-16-1-0455]
dc.description.sponsorshipTisch Cancer Institute (Cancer Center Grant) [P30 CA196521]
dc.description.sponsorshipNIH [DK56621]
dc.description.sponsorshipAmerican Association for the Study of Liver Diseases Foundation (AASLDF) Alan Hofmann Clinical and Translational Award
dc.identifier.citationONCOGENE, v.37, n.27, p.3740-3752, 2018
dc.identifier.doi10.1038/s41388-018-0206-3
dc.identifier.eissn1476-5594
dc.identifier.issn0950-9232
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/28274
dc.language.isoeng
dc.publisherNATURE PUBLISHING GROUP
dc.relation.ispartofOncogene
dc.rightsrestrictedAccess
dc.rights.holderCopyright NATURE PUBLISHING GROUP
dc.subject.othercirculating tumor dna
dc.subject.othercell-free dna
dc.subject.otherpotential therapeutic targets
dc.subject.otherdroplet digital pcr
dc.subject.otherliquid biopsy
dc.subject.otherintratumoral heterogeneity
dc.subject.othercolorectal-cancer
dc.subject.otherclonal evolution
dc.subject.otherlung-cancer
dc.subject.othercopy number
dc.subject.wosBiochemistry & Molecular Biology
dc.subject.wosOncology
dc.subject.wosCell Biology
dc.subject.wosGenetics & Heredity
dc.titleA pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countrySuíça
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryEspanha
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryisoch
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisoes
hcfmusp.affiliation.countryisode
hcfmusp.affiliation.countryisoca
hcfmusp.author.externalLABGAA, Ismail:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Lausanne Univ Hosp CHUV, Dept Visceral Surg, Lausanne, Switzerland
hcfmusp.author.externalVILLACORTA-MARTIN, Carlos:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA
hcfmusp.author.externalD'AVOLA, Delia:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Clin Univ Navarra, Liver Unit, Pamplona, Spain; Clin Univ Navarra, CIBEREHD, Pamplona, Spain
hcfmusp.author.externalCRAIG, Amanda J.:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA
hcfmusp.author.externalFELDEN, Johann von:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany
hcfmusp.author.externalSIA, Daniela:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA
hcfmusp.author.externalSTUECK, Ashley:Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA; Dalhousie Univ, Dept Pathol, Halifax, NS, Canada
hcfmusp.author.externalWARD, Stephen C.:Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA
hcfmusp.author.externalFIEL, M. Isabel:Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA
hcfmusp.author.externalMAHAJAN, Milind:Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
hcfmusp.author.externalTABRIZIAN, Parissa:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Dept Surg, New York, NY 10029 USA
hcfmusp.author.externalTHUNG, Swan N.:Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA
hcfmusp.author.externalANG, Celina:Icahn Sch Med Mt Sinai, Div Hematol & Med Oncol, Dept Med, New York, NY 10029 USA
hcfmusp.author.externalFRIEDMAN, Scott L.:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA
hcfmusp.author.externalLLOVET, Josep M.:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Univ Barcelona, Hosp Clin, Liver Canc Translat Res Lab, BCLC Grp,IDIBAPS,CIBEREHD, Catalonia, Spain; Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain
hcfmusp.author.externalSCHWARTZ, Myron:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Dept Surg, New York, NY 10029 USA
hcfmusp.author.externalVILLANUEVA, Augusto:Icahn Sch Med Mt Sinai, Dept Med, Liver Canc Program, Tisch Canc Inst,Grad Sch Biomed Sci,Div Liver Dis, New York, NY 10029 USA; Icahn Sch Med Mt Sinai, Div Hematol & Med Oncol, Dept Med, New York, NY 10029 USA
hcfmusp.citation.scopus83
hcfmusp.contributor.author-fmusphcSEBASTIAO NUNES MARTINS FILHO
hcfmusp.description.beginpage3740
hcfmusp.description.endpage3752
hcfmusp.description.issue27
hcfmusp.description.volume37
hcfmusp.origemWOS
hcfmusp.origem.pubmed29628508
hcfmusp.origem.scopus2-s2.0-85045124694
hcfmusp.origem.wosWOS:000437975200010
hcfmusp.publisher.cityLONDON
hcfmusp.publisher.countryENGLAND
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