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dc.contributor.authorvon Loga, K
dc.contributor.authorWoolston, A
dc.contributor.authorPunta, M
dc.contributor.authorBarber, LJ
dc.contributor.authorGriffiths, B
dc.contributor.authorSemiannikova, M
dc.contributor.authorSpain, G
dc.contributor.authorChalloner, B
dc.contributor.authorFenwick, K
dc.contributor.authorSimon, R
dc.contributor.authorMarx, A
dc.contributor.authorSauter, G
dc.contributor.authorLise, S
dc.contributor.authorMatthews, N
dc.contributor.authorGerlinger, M
dc.date.accessioned2019-12-06T15:10:07Z
dc.date.issued2020-01-16
dc.identifier.citationNature communications, 2020, 11 (1), pp. 139 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3447
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-019-13915-7
dc.description.abstractMismatch repair deficient (dMMR) gastro-oesophageal adenocarcinomas (GOAs) show better outcomes than their MMR-proficient counterparts and high immunotherapy sensitivity. The hypermutator-phenotype of dMMR tumours theoretically enables high evolvability but their evolution has not been investigated. Here we apply multi-region exome sequencing (MSeq) to four treatment-naive dMMR GOAs. This reveals extreme intratumour heterogeneity (ITH), exceeding ITH in other cancer types >20-fold, but also long phylogenetic trunks which may explain the exquisite immunotherapy sensitivity of dMMR tumours. Subclonal driver mutations are common and parallel evolution occurs in RAS, PIK3CA, SWI/SNF-complex genes and in immune evasion regulators. MSeq data and evolution analysis of single region-data from 64 MSI GOAs show that chromosome 8 gains are early genetic events and that the hypermutator-phenotype remains active during progression. MSeq may be necessary for biomarker development in these heterogeneous cancers. Comparison with other MSeq-analysed tumour types reveals mutation rates and their timing to determine phylogenetic tree morphologies.
dc.formatElectronic
dc.format.extent139 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleExtreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-12-05
rioxxterms.versionofrecord10.1038/s41467-019-13915-7
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-01-16
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.publication-statusPublished
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamTranslational Oncogenomicsen_US
dc.contributor.icrauthorSemiannikova, Mariaen
dc.contributor.icrauthorChalloner, Benjaminen
dc.contributor.icrauthorBarber, Louiseen
dc.contributor.icrauthorvon Loga, Katharinaen
dc.contributor.icrauthorGerlinger, Marcoen
dc.contributor.icrauthorLise, Stefanoen


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