title: Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas.
abstract: BACKGROUND
  Inhibitors of fibroblast growth factor receptors (FGFRs) have recently arisen as a promising treatment option for patients with FGFR alterations. Gene fusions involving FGFR3 and transforming acidic coiled-coil protein 3 (TACC3) have been detected in diffuse gliomas and other malignancies, and fusion-positive cases have responded well to FGFR inhibition. As high FGFR3 expression has been detected in fusion-positive tumors, we sought to determine the clinical significance of FGFR3 protein expression level as well as its potential for indicating FGFR3 fusions.
  
  
  METHODS
  We performed FGFR3 immunohistochemistry on tissue microarrays containing 676 grades II-IV astrocytomas and 116 grades II-III oligodendroglial tumor specimens. Fifty-one cases were further analyzed using targeted sequencing.
  
  
  RESULTS
  Moderate to strong FGFR3 staining was detected in gliomas of all grades, was more common in females, and was associated with poor survival in diffuse astrocytomas. Targeted sequencing identified FGFR3-TACC3 fusions and an FGFR3-CAMK2A fusion in 10 of 15 strongly stained cases, whereas no fusions were found in 36 negatively to moderately stained cases. Fusion-positive cases were predominantly female and negative for IDH and EGFR/PDGFRA/MET alterations. These and moderately stained cases show lower MIB-1 proliferation index than negatively to weakly stained cases. Furthermore, stronger FGFR3 expression was commonly observed in malignant tissue regions of lower cellularity in fusion-negative cases. Importantly, subregional negative FGFR3 staining was also observed in a few fusion-positive cases.
  
  
  CONCLUSIONS
  Strong FGFR3 protein expression is indicative of FGFR3 fusions and may serve as a clinically applicable predictive marker for treatment regimens based on FGFR inhibitors.
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Kirsi J
authors.initials: KJ
authors.lastname: Granberg
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Lehtinen
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Juha
authors.initials: J
authors.lastname: Kesseli
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Joonas
authors.initials: J
authors.lastname: Haapasalo
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Pekka
authors.initials: P
authors.lastname: Ruusuvuori
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Olli
authors.initials: O
authors.lastname: Yli-Harja
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Science Center, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories Ltd., Tampere University Hospital, Tampere, Finland; Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland; Pori unit, Tampere University of Technology, Pori, Finland; Department of Pathology, University of Tampere, Tampere, Finland; Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D050596:Oncogene Fusion; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
keywords: biomarker; gene fusion; glioblastoma; targeted sequencing