O6.07 * FGFR3-TACC3 AND EGFR-SEPT14 GENE FUSIONS IN ADULT GLIOMAS

Abstract

Novel chromosomal rearrangements involving tyrosine-kinase receptors FGFR3 and EGFR and resulting in actionable fusion proteins with strong oncogenic activity have been recently described in glioblastoma (GBM). 602 gliomas [380 grade IV (GBM), 116 grade III, 106 grade II] from the Pitie-Salpetriere brain tumor bank “Onconeurotheque” were analyzed for the presence of FGFR3-TACC3 and EGFR-SEPT14 by RT-PCR and sequencing . We identified 30 patients with fusion transcripts: 11 (8 GBM, one grade III, two grade II) with FGFR3-TACC3 and 19 (18 GBM and one grade III) with EGFR-SEPT14 fusion, including a GBM patient recurring after standard treatment. None of the 144 IDH1 mutated and 12 IDH2 mutated gliomas (including 28 GBM) had FGFR3-TACC3 or EGFR-SEPT14 fusions (P < 0.0002). EGFR-SEPT14 was associated with EGFR amplification 13/16 cases (81%) (12/14 in GBM EGFR-SEPT14+ vs 79/207 in GBM EGFR-SEPT14-, P = 0.001) and with EGFR vIII variant in 8/15 (53%), whereas none of the FGFR3-TACC3 fusions had EGFR abnormalities (0/8 in GBM FGFR3-TACC3+ vs 79/207 in GBM FGFR3-TACC3-, P = 0.027). Of particular interest, FGFR3-TACC3 positive tumors showed a very strong, diffuse and homogeneous FGFR3 expression by immunostaining, in contrast to fusion negative tumors, suggesting that FGFR3-TACC3 protein is expressed in nearly all tumor cells. In GBM patients, median overall survival was 32.80 months for FGFR3-TACC3+ patients, 25.50 months for EGFR-SEPT14+ patients compared to 17.20 for the other GBM patients (P = 0.60; NS). In conclusion we found that these gene fusions are not restricted to GBM but involve also grade II and III IDH wild-type tumors. Due to their oncogenic activity these genes fusions define a subset of patients that could benefit from specific molecular targeting at recurrence. We are now planning anti-FGFR and anti-EGFR treatment in this preselected population.