title: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
abstract: Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.
  
  
  
  We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).
  
  
  
  Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.
  
  
  
  PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Margaretha G M
authors.initials: MG
authors.lastname: Roemer
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Redd
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Heather
authors.initials: H
authors.lastname: Homer
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Courtney F
authors.initials: CF
authors.lastname: Connelly
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Daadi
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Daphne
authors.initials: D
authors.lastname: de Jong
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Hoppe
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Margaretha G.M. Roemer, Robert A. Redd, Heather Homer, Courtney F. Connelly, Gordon J. Freeman, Philippe Armand, Bjoern Chapuy, Donna S. Neuberg, and Margaret A. Shipp, Dana-Farber Cancer Institute; Azra H. Ligon, Heather H. Sun, and Scott J. Rodig, Brigham and Women's Hospital, Boston, MA; Margaretha G.M. Roemer and Daphne de Jong, VU University Medical Center, Amsterdam, the Netherlands; and Ranjana H. Advani, Yasodha Natkunam, Sarah E. Daadi, and Richard T. Hoppe, Stanford University Medical Center, Stanford, CA. margaret_shipp@dfci.harvard.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000032:analysis / Q000235:genetics*; D001761:Bleomycin / Q000627:therapeutic use; D059248:Chemoradiotherapy; D002869:Chromosome Aberrations; D002899:Chromosomes, Human, Pair 9; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005784:Gene Amplification; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008466:Mechlorethamine / Q000627:therapeutic use; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone / Q000627:therapeutic use; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000032:analysis / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome; D014747:Vinblastine / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D001761:Bleomycin; D008466:Mechlorethamine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D011241:Prednisone