title: The tumor virus landscape of AIDS-related lymphomas.
abstract: Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV-positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients.
authors.affiliation: Department of Immunology and Microbial Pathogenesis, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Aaron
authors.initials: A
authors.lastname: Arvey
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Akinyemi I
authors.identifier: http://orcid.org/0000-0003-0755-3639
authors.initials: AI
authors.lastname: Ojesina
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Gianna
authors.initials: G
authors.lastname: Ballon
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Joonil
authors.initials: J
authors.lastname: Jung
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Fujiko
authors.initials: F
authors.lastname: Duke
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, Siena, Italy; and.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoncini
authors.affiliation: Department of Human Pathology and Oncology, University of Siena, Siena, Italy; and.
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Eric
authors.initials: E
authors.lastname: Bressman
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Department of Pathology, Northwestern University, Chicago, IL.
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.affiliation: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Ethel
authors.identifier: http://orcid.org/0000-0003-3303-6299
authors.initials: E
authors.lastname: Cesarman
mesh_terms: D002472:Cell Transformation, Viral; D016000:Cluster Analysis; D015331:Cohort Studies; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000209:etiology* / Q000473:pathology; D009858:Oncogenic Viruses / Q000235:genetics / Q000276:immunology; D014412:Tumor Virus Infections / Q000150:complications*
references.citation: J Natl Cancer Inst Monogr. 1998;(23):95-100
references.pmid: 9709310
references.citation: Leuk Lymphoma. 1998 Aug;30(5-6):515-24
references.pmid: 9711914
references.citation: BMJ. 1999 Jul 3;319(7201):23-4
references.pmid: 10390454
references.citation: Arch Intern Med. 2005 Feb 28;165(4):416-23
references.pmid: 15738371
references.citation: Science. 2008 Feb 22;319(5866):1096-100
references.pmid: 18202256
references.citation: J Gen Virol. 2008 Apr;89(Pt 4):866-77
references.pmid: 18343826
references.citation: Ann Intern Med. 2008 May 20;148(10):728-36
references.pmid: 18490686
references.citation: Int J Cancer. 2008 Nov 1;123(9):2105-12
references.pmid: 18688856
references.citation: J Virol. 2009 Apr;83(8):3968-76
references.pmid: 19193789
references.citation: Blood. 2005 Dec 15;106(13):4345-50
references.pmid: 16131568
references.citation: J Immunol. 2012 Apr 1;188(7):3247-56
references.pmid: 22387550
references.citation: Nat Methods. 2012 Apr;9(4):357-9
references.pmid: 22388286
references.citation: Cell Host Microbe. 2012 Aug 16;12(2):233-45
references.pmid: 22901543
references.citation: Nature. 2012 Oct 4;490(7418):116-20
references.pmid: 22885699
references.citation: Immunol Rev. 2013 Jul;254(1):78-101
references.pmid: 23772616
references.citation: PLoS Pathog. 2014 Nov;10(11):e1004437
references.pmid: 25412476
references.citation: Virology. 2015 Jan 1;474:117-30
references.pmid: 25463610
references.citation: AIDS. 2009 Nov 13;23(17):2337-45
references.pmid: 19741479
references.citation: Am J Pathol. 2000 Jan;156(1):1-3
references.pmid: 10623645
references.citation: J Natl Cancer Inst. 2000 Nov 15;92(22):1823-30
references.pmid: 11078759
references.citation: Oncology (Williston Park). 2002 Apr;16(4):441-51, 456, 459
references.pmid: 12017534
references.citation: Int J Cancer. 2002 Jun 10;99(5):635-43
references.pmid: 12115495
references.citation: Lancet Oncol. 2003 Jan;4(1):22-9
references.pmid: 12517536
references.citation: Blood. 2003 Mar 15;101(6):2363-7
references.pmid: 12424193
references.citation: N Engl J Med. 1989 Oct 19;321(16):1080-5
references.pmid: 2552313
references.citation: Blood. 2005 Dec 15;106(13):4339-44
references.pmid: 16076866
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Int J Cancer. 2006 Jun 15;118(12):3030-44
references.pmid: 16404738
references.citation: J Gen Virol. 2006 Oct;87(Pt 10):2885-90
references.pmid: 16963746
references.citation: J Natl Cancer Inst. 2007 Jun 20;99(12):962-72
references.pmid: 17565153
references.citation: Lancet. 2007 Jul 7;370(9581):59-67
references.pmid: 17617273
references.citation: J Clin Oncol. 2009 Oct 20;27(30):5039-48
references.pmid: 19752343
references.citation: Nat Biotechnol. 2010 May;28(5):511-5
references.pmid: 20436464
references.citation: Br J Cancer. 2010 Jul 27;103(3):416-22
references.pmid: 20588274
references.citation: Clin Infect Dis. 2010 Oct 15;51(8):957-62
references.pmid: 20825305
references.citation: Nat Rev Cancer. 2010 Dec;10(12):878-89
references.pmid: 21102637
references.citation: J Med Virol. 2011 Feb;83(2):311-6
references.pmid: 21181928
references.citation: Cancer Lett. 2011 Jun 28;305(2):163-74
references.pmid: 21493001
references.citation: Nat Biotechnol. 2011 May;29(5):393-6
references.pmid: 21552235
references.citation: Bioinformatics. 2011 Jun 15;27(12):1739-40
references.pmid: 21546393
references.citation: Nat Biotechnol. 2011 Jul;29(7):644-52
references.pmid: 21572440
references.citation: Genome Res. 2012 Feb;22(2):292-8
references.pmid: 22009990
references.citation: Science. 1994 Dec 16;266(5192):1865-9
references.pmid: 7997879
references.citation: J Infect Dis. 1996 Mar;173(3):529-35
references.pmid: 8627013
references.citation: J Infect Dis. 1998 Jun;177(6):1705-9
references.pmid: 9607853