Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.

Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD.

Obsessive compulsive disorder (OCD) has a complex etiology that encompasses both genetic and environmental factors. However, to date, despite the identification of several promising candidate genes and linkage regions, the genetic causes of OCD are largely unknown. The objective of this study was to conduct linkage studies of childhood-onset OCD, which is thought to have the strongest genetic etiology, in several OCD-affected families from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The authors used parametric and non-parametric approaches to conduct genome-wide linkage analyses using 5,786 single nucleotide repeat polymorphisms (SNPs) in three CVCR families with multiple childhood-onset OCD-affected individuals. We identified areas of suggestive linkage (LOD score ≥ 2) on chromosomes 1p21, 15q14, 16q24, and 17p12. The strongest evidence for linkage was on chromosome 15q14 (LOD = 3.13), identified using parametric linkage analysis with a recessive model, and overlapping a region identified in a prior linkage study using a Caucasian population. Each CVCR family had a haplotype that co-segregated with OCD across a ~7 Mbp interval within this region, which contains 18 identified brain expressed genes, several of which are potentially relevant to OCD. Exonic sequencing of the strongest candidate gene in this region, the ryanodine receptor 3 (RYR3), identified several genetic variants of potential interest, although none co-segregated with OCD in all three families. These findings provide evidence that chromosome 15q14 is linked to OCD in families from the CVCR, and supports previous findings to suggest that this region may contain one or more OCD susceptibility loci.