Abstract
Prognostic molecular subgrouping of glioblastoma is an ongoing effort and the current classification includes IDH-wild-type and IDH-mutant entities, the latter showing significantly better prognosis. We performed a comparative integrated analysis of the FGFR glioblastoma subgroup consisting of 5 cases from a prospective 101-patient-cohort. FGFR alterations included FGFR2-TACC2 and FGFR2 amplifications arising in a multifocal IDH-mutant glioblastoma with unexpected 2.5-month patient survival, novel FGFR3 carboxy-terminal duplication and FGFR3-TLN1 fusion, and two previously described FGFR3-TACC3 fusions. The FGFR2 tumors showed additional mutations in SERPINE1/PAI-1 and MMP16, as part of extensive extracellular matrix remodeling programs. Whole transcriptomic analysis revealed common proliferation but distinct morphogenetic gene expression programs that correlated with tumor histology. The kinase program revealed EPHA3, LTK and ALK receptor tyrosine kinase overexpression in individual FGFR tumors. Paradoxically, all FGFR-fused glioblastomas shared strong PI3K and MAPK pathway suppression effected by SPRY, DUSP and AKAP12 inhibitors, whereas the FGFR2-TACC2 tumor elicited also EGFR suppression by ERRFI1 upregulation. This integrated analysis outlined the proliferation and morphogenetic expression programs in FGFR glioblastoma, and identified four novel, clinically targetable FGFR2 and FGFR3 alterations that confer aggressive phenotype and trigger canonical pathway feedback inhibition, with important therapeutic implications.
Highlights
Glioblastoma is the most frequent malignant primary brain neoplasm in adults, with an incidence of 3–4 cases per 100,000 population, and 41% survival at 1 year [1]
Most Isocitrate dehydrogenase (IDH)-mutant cases conform to this biological behavior, we describe here the first case of de novo IDH-mutant glioblastoma with FGFR2 alterations that induced fulminant progression with LM spread, resembling the most aggressive cases of IDH-wild-type glioblastoma
We found that the multifocal FGFR2 tumors exhibited relatively unique morphogenetic programs, whereas the four FGFR3 IDH-wild-type tumors showed relative histologic and signaling homogeneity
Summary
Glioblastoma is the most frequent malignant primary brain neoplasm in adults, with an incidence of 3–4 cases per 100,000 population, and 41% survival at 1 year [1]. The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) comprises four members that share a common structure and activate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol 3′-OH kinase (PI3K)/AKT pathways by constitutively docking FGFR substrate 2 (FRS2) to the juxtamembrane receptor region. They activate STATs and phospholipase (PL) C-γ by docking them to phosphorylated tyrosine residues, the latter within the carboxyl (C)-terminal tail of the receptor [5]. The FGFR3-TACC3 fusions are the FGFR alterations most commonly occurring in IDHwild-type glioblastoma [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
