Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

dc.contributorWeill Cornell Medical College
dc.contributorTri-Institutional Training Program in Computational Biology and Medicine
dc.contributorNorthwestern University
dc.contributorRush University Medical Center
dc.contributorUniversidade Estadual Paulista (Unesp)
dc.contributorIcahn School of Medicine at Mount Sinai
dc.contributorHumanitas Clinical and Research Center
dc.contributorUniversity of Milan
dc.creatorReichel, Jonathan
dc.creatorChadburn, Amy
dc.creatorRubinstein, Paul G.
dc.creatorGiulino-Roth, Lisa
dc.creatorTam, Wayne
dc.creatorLiu, Yifang
dc.creatorGaiolla, Rafael [UNESP]
dc.creatorEng, Kenneth
dc.creatorBrody, Joshua
dc.creatorInghirami, Giorgio
dc.creatorCarlo-Stella, Carmelo
dc.creatorSantoro, Armando
dc.creatorRahal, Daoud
dc.creatorTotonchy, Jennifer
dc.creatorElemento, Olivier
dc.creatorCesarman, Ethel
dc.creatorRoshal, Mikhail
dc.date2015-10-21T13:08:51Z
dc.date2015-10-21T13:08:51Z
dc.date2015-02-12
dc.date.accessioned2023-09-12T06:32:08Z
dc.date.available2023-09-12T06:32:08Z
dc.identifierhttp://www.bloodjournal.org/content/125/7/1061?sso-checked=true
dc.identifierBlood. Washington: Amer Soc Hematology, v. 125, n. 7, p. 1061-1072, 2015.
dc.identifier0006-4971
dc.identifierhttp://hdl.handle.net/11449/128305
dc.identifier10.1182/blood-2014-11-610436
dc.identifierWOS:000350818800007
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8777657
dc.descriptionClassical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. beta-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.
dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.descriptionWeill Cornell Medical College, Department of Pathology and Laboratory Medicine
dc.descriptionNorthwestern University, Department of Pathology, Feinberg School of Medicine
dc.descriptionRush University Medical Center, John H. Stroger Jr Hospital of Cook County
dc.descriptionWeill Cornell Medical College, Department of Pediatrics
dc.descriptionHumanitas Clinical and Research Center, Humanitas Cancer Center
dc.descriptionUniversity of Milan, School of Medicine
dc.descriptionWeill Cornell Medical College, Institute for Computational Biomedicine
dc.descriptionUniversidade Estadual Paulista, Departamento de Clínica Médica, Faculdade de Medicina de Botucatu
dc.format1061-1072
dc.languageeng
dc.publisherAmer Soc Hematology
dc.relationBlood
dc.relation15.132
dc.relation6,434
dc.rightsAcesso restrito
dc.sourceWeb of Science
dc.titleFlow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells
dc.typeArtigo


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