Case Report: Next generation sequencing identifies a NAB2-STAT6 fusion in Glioblastoma

Abstract

Background: Molecular profiling has uncovered genetic subtypes of glioblastoma (GBM), including tumors with IDH1 mutations that confer increase survival and improved response to standard-of-care therapies. By mapping the genetic landscape of brain tumors in routine clinical practice, we enable rapid identification of targetable genetic alterations.

Case presentation: A 29-year-old male presented with new onset seizures prompting neuroimaging studies, which revealed an enhancing 5 cm intra-axial lesion involving the right parietal lobe. He underwent a subtotal resection and pathologic examination revealed glioblastoma with mitoses, microvascular proliferation and necrosis. Immunohistochemical (IHC) analysis showed diffuse expression of GFAP, OLIG2 and SOX2 consistent with a tumor of glial lineage. Tumor cells were positive for IDH1(R132H) and negative for ATRX. Clinical targeted-exome sequencing (DFBWCC Oncopanel) identified multiple functional variants including IDH1 (p.R132H), TP53 (p.Y126_splice), ATRX (p.R1302fs*), HNF1A (p.R263H) and NF1 (p.H2592del) variants and a NAB2-STAT6 gene fusion event involving NAB2 exon 3 and STAT6 exon 18. Array comparative genomic hybridization (aCGH) further revealed a focal amplification of NAB2 and STAT6. IHC analysis demonstrated strong heterogenous STAT6 nuclear localization (in 20 % of tumor cells).

Conclusions: While NAB2:STAT6 fusions are common in solitary fibrous tumors (SFT), we report this event for the first time in a newly diagnosed, secondary-type GBM or any other non-SFT. Our study further highlights the value of comprehensive genomic analyses in identifying patient-specific targetable mutations and rearrangements.

Fig. 1

a Coronal T2 FLAIR highlights the intra-parenchymal location of the complex tumor resection bed and associated edema. b Axial post contrast T1 MRI showing peripheral ring enhancement and progression from previous post-surgical imaging (right). c H&E sections showing a hypercellular fibrillary neoplasm with morphological atypia, mitoses, and endothelial proliferation. Necrosis was also present (not shown). The tumor showed diffuse expression of the glial markers Olig2, Sox2 and GFAP. Immunoreactivity with antibody against the R132H IDH1 mutation. ATRX immunostaining highlighting loss within the tumor and normal retained expression in a adjacent vessel. Immunohistochemistry with the STAT6 antibody showing strong nuclear expression in 15–20 % of tumor nuclei (inset) consistent with previous described function of NAB2-STAT6 fusion event. d Schematic demonstrating the locations of common NAB2-STAT6 rearrangements in solitary fibrous tumor (SFTs), the presented case GBM and other STAT6 rearrangements reported in GBMs