title: Targetable genetic features of primary testicular and primary central nervous system lymphomas.
abstract: Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Margaretha G M
authors.initials: MG
authors.lastname: Roemer
authors.affiliation: Broad Institute, Cambridge, MA;
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Liye
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Broad Institute, Cambridge, MA;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dunford
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: David M
authors.initials: DM
authors.lastname: Meredith
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Center of Gynaecologic Oncology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pathology, Hannover Medical School, Hannover, Germany;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Feuerhake
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ducar
authors.affiliation: Department of Hematology and Oncology, University Hospital Freiburg, Freiburg, Germany;
authors.forename: Gerald
authors.initials: G
authors.lastname: Illerhaus
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Daniel
authors.initials: D
authors.lastname: Gusenleitner
authors.affiliation: Massachusetts General Hospital/North Shore Cancer Center, Danvers, MA;
authors.forename: Erica A
authors.initials: EA
authors.lastname: Linden
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Heather
authors.initials: H
authors.lastname: Homer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Miyuki
authors.initials: M
authors.lastname: Aono
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Pinkus
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Ferry
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: van Hummelen
authors.affiliation: Broad Institute, Cambridge, MA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Broad Institute, Cambridge, MA; Department of Pathology, Massachusetts General Hospital, Boston, MA; and.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA;
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands;
authors.forename: Daphne
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA;
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic
chemical_list: D009363:Neoplasm Proteins