Strong FGFR3 Staining Is a Marker for FGFR3 Fusions in Diffuse Gliomas

Neuro Oncol. 2017 Sep 1;19(9):1206-1216. doi: 10.1093/neuonc/nox028.

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.

Keywords: biomarker; gene fusion; glioblastoma; targeted sequencing.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Brain Neoplasms / genetics*
  • Child
  • Child, Preschool
  • Female
  • Glioma / genetics*
  • Humans
  • Male
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Oncogene Fusion
  • Receptor, Fibroblast Growth Factor, Type 3 / analysis
  • Receptor, Fibroblast Growth Factor, Type 3 / biosynthesis*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Microtubule-Associated Proteins
  • TACC3 protein, human
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3