Genomic analyses reveal the common origins and pathogenesis of dysembryoplastic neuroepithelial tumors and their satellite lesions

Pediatric low-grade gliomas (LGGs) harbor different clinical and molecular characteristics from their adult counterparts. Numerous Pediatric LGGs have the propensity to develop intractable epilepsy without tumor progression, and Dysembryoplastic neuroepithelial tumor (DNET) is regarded as the prototype of such tumors. More than half of DNETs consist of tiny nodular lesions in the subcortical white matter that are separated from the main mass- a satellite lesion (SL). The existence of SLs hasve shown a high association with persistent seizures despite complete removal of all lesions, implicating that the tumor may be primed to develop during the embryogenesis. Moreover, recent genomic studies support that an alteration of FGFR1 areis one of the initiating events in the pathogenesis of DNETs. To elucidate pathogenesis and tumor evolution by investigating the relationship between and SLs and the main mass, we performed comparative lesion sequencing and phylogenetic analysis. Separate biopsy samples from the main masses and SLs of 3 patients with DNET and one patient with extraventricular neurocystoma (EVN) were analyzed. As a result, FGFR1 K656E and K655I mutations were harbored as compound heterozygous in cis on DNET samples. All sequenced SLs in the samples had the same mutations as the main mass. For EVN, QKI-NTRK2 fusion was detected in RNA-seq and sharing of driving mutations was also observed. The Pphylogenic tree revealed that the tumor has no significant relation to space and time with the primary the main mass. Moreover, validation of the similarity and diversity indicated that main mass and its SLs were separated at an early stage in oncogenesis with shared FGFR1 alterations, and then they further expanded at different places. Our result may implicate that priming mutation in PLGG such as DNET of EVN arises in late cortical development during embryogenesis and later develop through concurrent second hit or some environmental cues.