title: Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class.
abstract: OBJECTIVE
  Tumor-infiltrating lymphocytes (TIL) have prognostic significance in many cancers, yet their roles in glioblastoma have not been fully defined. We hypothesized that TILs in glioblastoma are associated with molecular alterations, histologies, and survival.
  
  
  METHODS
  We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic, and clinical correlates of TILs in glioblastomas. Lymphocytes were categorized as absent, present, or abundant in histopathologic images from 171 TCGA glioblastomas. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. We validated histologic findings using CD3G gene expression.
  
  
  RESULTS
  We found a positive correlation between TILs and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Conversely, TILs were rare in glioblastomas with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGF receptor (EGFR)-amplified and homozygous PTEN-deleted glioblastomas. These alterations are characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association with survival was shown.
  
  
  CONCLUSIONS
  TILs were enriched in glioblastomas of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified, and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations.
authors.affiliation: Authors' Affiliations: Emory University School of Medicine, Departments of Biomedical Informatics and Pathology and Laboratory Medicine,Center for Comprehensive Informatics, Winship Cancer Institute, Emory University; Department of Pathology, Children's Healthcare of Atlanta, Atlanta, Georgia; Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan; Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Pathology, Duke University Medical Center, Durham, North Carolina; Department of Pathology, Ohio State University, Columbus, Ohio; Department of Pathology, University of North Carolina, Chapel Hill, North Carolina; and Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: W Caleb
authors.initials: WC
authors.lastname: Rutledge
authors.forename: Jun
authors.initials: J
authors.lastname: Kong
authors.forename: Jingjing
authors.initials: J
authors.lastname: Gao
authors.forename: David A
authors.initials: DA
authors.lastname: Gutman
authors.forename: Lee A D
authors.initials: LA
authors.lastname: Cooper
authors.forename: Christina
authors.initials: C
authors.lastname: Appin
authors.forename: Yuna
authors.initials: Y
authors.lastname: Park
authors.forename: Lisa
authors.initials: L
authors.lastname: Scarpace
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schniederjan
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: Joel H
authors.initials: JH
authors.lastname: Saltz
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor