Show simple item record

dc.contributor.authorSchmitz, Rolanden
dc.contributor.authorWright, George Wen
dc.contributor.authorHuang, Da Weien
dc.contributor.authorJohnson, Calvin Aen
dc.contributor.authorPhelan, James Den
dc.contributor.authorWang, James Qen
dc.contributor.authorRoulland, Sandrineen
dc.contributor.authorKasbekar, Monicaen
dc.contributor.authorYoung, Ryan Men
dc.contributor.authorShaffer, Arthur Len
dc.contributor.authorHodson, Danielen
dc.contributor.authorXiao, Wenmingen
dc.contributor.authorYu, Xinen
dc.contributor.authorYang, Yandanen
dc.contributor.authorZhao, Hongen
dc.contributor.authorXu, Weihongen
dc.contributor.authorLiu, Xueluen
dc.contributor.authorZhou, Binen
dc.contributor.authorDu, Weien
dc.contributor.authorChan, Wing Cen
dc.contributor.authorJaffe, Elaine Sen
dc.contributor.authorGascoyne, Randy Den
dc.contributor.authorConnors, Joseph Men
dc.contributor.authorCampo, Eliasen
dc.contributor.authorLopez-Guillermo, Armandoen
dc.contributor.authorRosenwald, Andreasen
dc.contributor.authorOtt, Germanen
dc.contributor.authorDelabie, Janen
dc.contributor.authorRimsza, Lisa Men
dc.contributor.authorTay Kuang Wei, Kevinen
dc.contributor.authorZelenetz, Andrew Den
dc.contributor.authorLeonard, John Pen
dc.contributor.authorBartlett, Nancy Len
dc.contributor.authorTran, Baoen
dc.contributor.authorShetty, Jyotien
dc.contributor.authorZhao, Yongmeien
dc.contributor.authorSoppet, Dan Ren
dc.contributor.authorPittaluga, Stefaniaen
dc.contributor.authorWilson, Wyndham Hen
dc.contributor.authorStaudt, Louis Men
dc.date.accessioned2018-06-12T13:32:47Z
dc.date.available2018-06-12T13:32:47Z
dc.date.issued2018-04en
dc.identifier.issn0028-4793
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276939
dc.description.abstractBACKGROUND Diffuse large B cell lymphomas (DLBCL) are phenotypically and genetically heterogeneous. Gene expression profiling identified subgroups of DLBCL (activated B-cell [ABC], germinal center B-cell [GCB], and Unclassified) based on cell-of-origin that are associated with differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS We studied 574 DLBCL biopsies using exome and transcriptome sequencing, array-based DNA copy number analysis and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on co-occurrence of genetic alterations. RESULTS We identified four prominent genetic subtypes in DLBCL termed MCD (based on co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguish each genetic subtype from other DLBCLs. These subtypes differ phenotypically, as judged by gene expression signatures, and by their response to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Genetic pathway analysis suggests that MCD and BN2 DLBCLs rely on chronic active B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a nosology for precision medicine strategies in DLBCL. (Funded by Intramural Research Program of the NIH, Center for Cancer Research, and the National Cancer Institute)
dc.description.sponsorshipThis research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute and by a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures (SPECS II) grant (5U01CA157581-05). R.S. was supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). D.J.H. was a Kay Kendall Leukaemia Fund Intermediate research fellow. M.K. was supported by the National Institutes of Health Oxford-Cambridge Scholars Program and the Washington University in St. Louis Medical Scientist Training Program
dc.format.mediumPrinten
dc.languageengen
dc.publisherMassachusetts Medical Society
dc.subjectHumansen
dc.subjectAntineoplastic Combined Chemotherapy Protocolsen
dc.subjectBiopsyen
dc.subjectPrognosisen
dc.subjectGene Expression Profilingen
dc.subjectSequence Analysis, DNAen
dc.subjectEpigenesis, Geneticen
dc.subjectGenotypeen
dc.subjectGenetic Heterogeneityen
dc.subjectMutationen
dc.subjectLymphoma, Large B-Cell, Diffuseen
dc.subjectKaplan-Meier Estimateen
dc.subjectTranscriptomeen
dc.subjectExomeen
dc.titleGenetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.en
dc.typeArticle
prism.endingPage1407
prism.issueIdentifier15en
prism.publicationDate2018en
prism.publicationNameThe New England journal of medicineen
prism.startingPage1396
prism.volume378en
dc.identifier.doi10.17863/CAM.24220
dcterms.dateAccepted2018-03-06en
rioxxterms.versionofrecord10.1056/nejmoa1801445en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-04en
dc.contributor.orcidHodson, Daniel [0000-0001-6225-2033]
dc.contributor.orcidDelabie, Jan [0000-0001-5023-0689]
dc.contributor.orcidBartlett, Nancy L [0000-0001-8470-394X]
dc.identifier.eissn1533-4406
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MR/M008584/1)
cam.orpheus.successThu Jan 30 13:00:46 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record