EvaluatingH3F3AK27M and G34R/V somatic mutations in a cohort of pediatric brain tumors of different and rare histologies

Purpose Somatic mutations on H3 histone are currently considered a genetic hallmark for midline pediatric high-grade gliomas (HGGs). Yet, different tumor histologies have been occasionally described to carry these mutations. Since histone modifications can lead to major epigenetic changes with direct impact on prognosis and treatment, we thought to investigate the occurrence ofH3F3AK27M and G34R/V mutations in a cohort of pediatric tumors which included HGGs, low-grade gliomas, ependymomas, medulloblastomas, and a series of rare brain tumor lesions of different histologies. Methods A total of 82 fresh-frozen pediatric brain tumor samples were evaluated. PCR or RT-PCR followed by Sanger sequencing for the exon 2 ofH3F3A(containing both K27 and G34 hotspots) were obtained and aligned to human genome. Loss of trimethylation mark (H3K27me3) inH3F3A/K27M-mutant samples was confirmed by immunohistochemistry. Results We foundH3F3A/K27M mutation in 2 out of 9 cases of HGGs; noH3F3A/K27M mutations were detected in low-grade gliomas (27), ependymomas (n= 10), medulloblastomas (n= 21), or a series of rare pediatric brain tumors which included meningiomas, dysembryoplastic neuroepithelial tumors (DNETs), central nervous system (CNS) germ-cell tumors, choroid plexus tumors, cortical hamartoma, subcortical tubers, and schwannomas (n= 15).H3F3A/G34R/V mutation was not observed in any of the samples. Conclusions Our investigation reinforces the low frequency ofH3F3Asomatic mutations outside the HGG setting. Interestingly, an atypical focal brainstem glioma carryingH3F3AK27M mutation that showed protracted clinical course with late-onset tumor progression was identified. (AU)