Alterations in PTPN11 and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

The PTPN11 gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations of PTPN11 and other RAS-/MAP-Kinase signaling pathway genes 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 the PTPN11 gene compared to GG with other common MAP-Kinase signaling pathway alterations. Seventy-two GG were submitted to whole exome sequencing and genotyping and 86 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. Clinical data were retrieved from hospital files including postsurgical disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in FGFR4, RHEB, NF1, KRAS as well as BRAFV600E alterations. Histopathology revealed an atypical and complex glio-neuronal phenotype with subpial tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11 alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG with BRAFV600E mutations (85% Engel I). Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by PTPN11 and other Noonan syndrome-related alterations of the RAS-/MAP-Kinase signaling pathway. These findings need prospective validation in clinical practice as they argue for an adapted WHO grading system in developmental, glio-neuronal tumors associated with early-onset focal epilepsy. These findings also open avenues for targeted medical treatment.