LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

Abstract

Background The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using Fresh Frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. Methods Analysis of patients age 0 to 21 years, enrolled in Germany between 04/2019 and 02/2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing and RNA-Seq were performed. Results FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n=71), BRAF V600E-mutation (n=12) and alterations in FGFR1 (n=14) as the most frequent alterations, among other common molecular drivers (n=12). . N=16 cases (13%) presented rare gene fusions (e.g. TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n=27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 ITD (n=6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. Conclusions The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients

“…Of all fibroblast growth factor receptor (FGFR)-altered pLGGs, 42% harbour FGFR1-ITDs (internal tandem duplications). 2 These epidemiological data support the idea that alterations in FGFR are relatively frequent in paediatric CNS tumours, which presents an opportunity to pharmacologically target FGFR. First promising results on treatment with FGFR inhibition in young glioma patients have been published within the RAGNAR study 3 and on Debio1347.…”

“…Activation of fibroblast growth factor (FGF) signalling is present in 4% of paediatric central nervous system (CNS) malignancies 1 and in up to 11% in the subgroup of paediatric low‐grade glioma (pLGG) patients. Of all fibroblast growth factor receptor ( FGFR )‐altered pLGGs, 42% harbour FGFR1 ‐ITDs (internal tandem duplications) 2 . These epidemiological data support the idea that alterations in FGFR are relatively frequent in paediatric CNS tumours, which presents an opportunity to pharmacologically target FGFR.…”

“…Recent in‐depth molecular analyses of large paediatric CNS tumour cohorts revealed that the prevalence of FGFR ‐ITDs in pLGG has been underestimated to date 2 . While mortality of these patients is low, a large proportion suffers from frequent recurrences and high disease morbidity 14,15 .…”

“…Recent in-depth molecular analyses of large paediatric CNS tumour cohorts revealed that the prevalence of FGFR-ITDs in pLGG has been underestimated to date. 2 While mortality of these patients is low, a large proportion suffers from frequent recurrences and high disease morbidity. 14,15 Preliminary data on low-grade tumours with FGFR alterations suggest a more aggressive behaviour when compared to low-grade tumours with KIAA1549:BRAF gene fusions, 16 highlighting the need for novel therapeutic approaches.…”

Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow

“…Informed consent for sample collection, use of material and clinical data was obtained within the study S-304/2014 (V2/V3), approved by the institutional review board of the University of Heidelberg. The primary patient tumor material was molecularly analyzed (DNA-methylation and gene panel sequencing) within the PTT2.0 study [ 15 ] or the LOGGIC Core co-clinical biobank [ 16 ]. Methylation scores were obtained via the brain tumor classifiers (V11b4, 12.3 or 12.5) ( www.molecularneuropathology.org ).…”