Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

AbstractExome-wide sequencing studies recently describedPTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations ofPTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of thePTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e.,BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG withPTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains inNF1, KRAS,FGFR4 andRHEB, as well asBRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG andPTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably differe...
Source: Acta Neuropathologica - Category: Neurology Source Type: research