Novel targetable FGFR2 and FGFR3 alterations in glioblastoma associate with aggressive phenotype and distinct gene expression programs

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.

Multi-Platform Classification of IDH-Wild-Type Glioblastoma Based on ERK/MAPK Pathway: Diagnostic, Prognostic and Therapeutic Implications

“…Tumor specimens, histology and, immunohistochemistry (IHC): Surgical resection, biopsy or autopsy specimens were obtained from patients with glioblastoma, as previously described, in accordance with hospital regulations [7,11,12]. With one exception, the IDH-wild-type cases illustrated in this study correspond to first-diagnosis, untreated tumors.…”

“…Next-generation sequencing (NGS) and copy number (CN) variation: Nucleic acids were extracted from FFPE samples, as previously described [11]. Variant analysis and interpretation following NGS using the xT 596-gene or xE whole-exome panels (Tempus Labs, Chicago, IL, USA) or the customized 295-gene panel were performed as previously described [7,11,12]. CN analysis was performed as previously described [7,14].…”

“…Variant analysis and interpretation following NGS using the xT 596-gene or xE whole-exome panels (Tempus Labs, Chicago, IL, USA) or the customized 295-gene panel were performed as previously described [7,11,12]. CN analysis was performed as previously described [7,14]. Gene amplification was called for CN ≥ 7, and loss of heterozygosity (LOH) for alterations with loss of one allele.…”

“…Phosphorylated ERKs translocate to the nucleus to activate transcription factors or remain cytoplasmic to activate substrates involved in cell growth. The pathway is negatively controlled upstream by direct inhibition through NF1, a Ras GTPase-activating protein (GAP) but also by feedback loops resulting from ERK-dependent transcription of the ERK phosphatases DUSP4/5/6 and the Sprouty family members [7][8][9][10]. In contrast, the PI3K/AKT/mTOR pathway is a heterogeneous pathway involving both protein and lipid signal transduction mediators and is directly inhibited by the PTEN tumor suppressor, acting upstream as phosphoinositide phosphatase counteracting the effect of PI3K [3].…”

Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers

“…discovered FGFR3-TACC3 , a canonical fusion across multiple solid tumors, in 1/80 TNBC tumors and in vitro studies indicate this fusion protein is a targetable driver in TNBC ( 34 ). FGFR2-TACC2 that has been described in glioblastoma ( 39 ), NSCLC ( 40 ) and cervical cancer ( 41 ), was first identified in breast cancer in our study. Table 2 also summarizes other previously reported RTK gene fusions in breast cancer that were not detected in our cohort.…”