title: Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva.
abstract: OBJECTIVE
  Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1.
  
  
  OBJECTIVE
  To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression.
  
  
  METHODS
  We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs.
  
  
  METHODS
  Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC.
  
  
  RESULTS
  Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women's Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy.
  
  
  CONCLUSIONS
  Recurrent copy number gain of the genes encoding the PD-1 ligands provides a genetic basis for PD-L1 expression in a subset of cervical and vulvar SCCs and identifies a class of patients that are rational candidates for therapies targeting PD-1.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts.
authors.forename: Margaretha G M
authors.initials: MG
authors.lastname: Roemer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Kelley
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Emeline
authors.initials: E
authors.lastname: Aviki
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Pak
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Courtney
authors.initials: C
authors.lastname: Connelly
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lee
authors.affiliation: Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Akila
authors.initials: A
authors.lastname: Viswanathan
authors.affiliation: Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neil
authors.initials: N
authors.lastname: Horowitz
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Lindeman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Frank
authors.initials: F
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D014846:Vulvar Neoplasms / Q000235:genetics*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein