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dc.contributor.authorHoang, PH
dc.contributor.authorDobbins, SE
dc.contributor.authorCornish, AJ
dc.contributor.authorChubb, D
dc.contributor.authorLaw, PJ
dc.contributor.authorKaiser, M
dc.contributor.authorHoulston, RS
dc.date.accessioned2019-02-20T08:11:28Z
dc.date.issued2018-11
dc.identifier.citationLeukemia, 2018, 32 (11), pp. 2459 - 2470
dc.identifier.issn0887-6924
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3069
dc.identifier.eissn1476-5551
dc.identifier.doi10.1038/s41375-018-0103-3
dc.description.abstractMultiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.
dc.formatPrint-Electronic
dc.format.extent2459 - 2470
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectMultiple Myeloma
dc.subjectCell Differentiation
dc.subjectRegulatory Sequences, Nucleic Acid
dc.subjectMutation
dc.subjectPolymorphism, Single Nucleotide
dc.subjectOncogenes
dc.subjectGenome, Human
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectPromoter Regions, Genetic
dc.subjectDNA Copy Number Variations
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectCarcinogenesis
dc.subjectWhole Genome Sequencing
dc.titleWhole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms.
dc.typeJournal Article
dcterms.dateAccepted2018-03-05
rioxxterms.versionofrecord10.1038/s41375-018-0103-3
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfLeukemia
pubs.issue11
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/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group
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
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group
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.publication-statusPublished
pubs.volume32
pubs.embargo.termsNot known
icr.researchteamCancer Genomicsen_US
icr.researchteamMolecular & Population Geneticsen_US
icr.researchteamMyeloma Groupen_US
dc.contributor.icrauthorHoang, Phucen
dc.contributor.icrauthorCornish, Alexanderen
dc.contributor.icrauthorLaw, Philipen
dc.contributor.icrauthorKaiser, Martinen
dc.contributor.icrauthorHoulston, Richarden


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