👤 Sanda Alexandrescu

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. Show less

Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-mutant but their significance has not been completely explored. We evaluated these associations in our institutional cohorts. We searched our archives for H3K2M7-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. We identified 81 patients (age range 2-68, median 26), of which 79 (97%) were DMGs, and 2 were glioneuronal tumors. The 2 glioneuronal tumors (1 with BRAF fusion and 1 BRAF-V600E-mutant) were removed from the outcome analysis. Four cases had BRAF V600E mutation, 12 had FGFR1 hotspot mutations, and one each had KRAS and NRAS pathogenic mutations. The most common correlating anatomic location was the brainstem for the BRAF group and thalamus for the FGFR1group. Follow-up ranged from 0 to 78 months, average 20.4 months. The overall survival in FGFR1- and BRAF V600E-mutant DMGs was not statistically improved when compared with those that were wildtype. However, the possibility of targeted therapy argues for comprehensive sequencing of H3K27-altered gliomas. Show less

This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP). We phenotyped and performed exome sequencing for 352 SUDP cases. We analyzed variants in 294 "SUDP genes" with mechanisms plausibly related to sudden death. In a subset of 73 cases with parental data (trios), we performed exome-wide analyses and conducted cohort-wide burden analyses. In total, we identified likely contributory variants in 37 of 352 probands (11%). Analysis of SUDP genes identified pathogenic/likely pathogenic variants in 12 of 352 cases (SCN1A, DEPDC5 [2], GABRG2, SCN5A [2], TTN [2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of unknown significance-favor-pathogenic in 17 of 352 cases. Exome-wide analyses of the 73 cases with family data additionally identified 4 de novo pathogenic/likely pathogenic variants (SCN1A [2], ANKRD1, and BRPF1) and 4 de novo variants of unknown significance-favor-pathogenic. Comparing cases with controls, we demonstrated an excess burden of rare damaging SUDP gene variants (odds ratio, 2.94; 95% confidence interval, 2.37-4.21) and of exome-wide de novo variants in the subset of 73 with trio data (odds ratio, 3.13; 95% confidence interval, 1.91-5.16). We provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death. Show less