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

Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

The study was supported by the German Research Foundation DFG Bl421/4-1 to IB; NU 50/13-1 to PN, and LA 4193/2-1 to DL. This work was supported by the DFG Research Infrastructure West German Genome Center (project 407493903) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the production site Cologne (Cologne Center for Genomics). SJ is supported by the Interdisziplinaeres Zentrum fuer Klinische Forschung, Universitaetsklinkum Erlangen (IZKF; project number J81).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of the Medical Faculty of the Friedrich-Alexander-University (FAU) Erlangen-Nuernberg, Germany, approved this study within the framework of the EU project DESIRE (FP7, grant agreement #602,531; AZ 92_14B) and European Reference Network EpiCARE (grant agreement #769,051; AZ 193_18B).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

The complete methylation data of the 86 samples included in this study, will be deposited in NCBIs Gene Expression Omnibus (GEO http://www.ncbi.nlm.nih.gov/geo). The accession numbers follow.

http://www.ncbi.nlm.nih.gov/geo

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