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

Abstract

Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 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 the PTPN11/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 with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E 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 and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.

The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D

“…While we have made considerable progress in understanding the molecular mechanisms of FCD ILAE Type 2, our current knowledge about clinical phenotypes and molecular signatures of patients with FCD ILAE Type 1 and 3 remains poor [ 4 , 13 ]. Following the recently proposed DNA methylation-based CNS tumor classification applying commercially available 850 K/EPIC arrays for DNA extracted from archival formalin-fixed and paraffin-embedded tissue specimens [ 9 ], there is now also an ongoing interest in DNA methylation patterns in surgical epilepsy specimens to help with the pathologic diagnosis and correlate molecular findings with the clinical history [ 17 , 19 , 21 ].With its established role in gene regulation, DNA methylation has further received attention as disease mechanism contributing to the pathogenesis of epilepsy and associated structural brain lesions [ 15 , 22 , 23 ]. Here, we attempt to comprehensively describe the DNA methylation signature from surgical brain tissues, primarily focusing on FCD ILAE Type 3D with neuronal loss in layer 4.…”

Long-term seizure outcome after epilepsy surgery of neuroglial tumors

“…These findings suggest that neuroglial tumors and FCDs may share molecular genetics and electrophysiological features much more similar than previously considered. Further elucidation of these phenomena, advancements in molecular classification, as recently described for specific cases of GG ( 47 ), and their correlation with postsurgical outcomes in future studies, will undoubtedly enhance our comprehension of the diversity of these lesions.…”

Mometasone Furoate Inhibits the Progression of Head and Neck Squamous Cell Carcinoma via Regulating Protein Tyrosine Phosphatase Non-Receptor Type 11

“…As a result, PTPN11 plays a central role in the activation of oncogenic signaling pathways, such as PI3K/AKT [12], RAS/Raf/MAPK [13] and Jak/STAT [14]. It is widely acknowledged that PTPN11 is highly expressed in many tumors [15], and its aberrant expression is closely related to a poorer prognosis in a range of tumors [16,17]. In HNSCC, PTPN11 is overexpressed and participates in the invasion and metastasis of cells via activating the ERK1/2-Snail/Twist1 pathway [18].…”