Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

Abstract

AbstractThePTPN11gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations ofPTPN11and otherRAS-/MAP-Kinase signaling pathwaygenescause 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 thePTPN11gene 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 withPTPN11alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains inFGFR4, RHEB, NF1, KRASas well asBRAFV600Ealterations. 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 andPTPN11alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG withBRAFV600Emutations (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 byPTPN11and other Noonan syndrome-related alterations of theRAS-/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.