Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes
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. He...
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Veröffentlicht in: | Acta neuropathologica 2023-06, Vol.145 (6), p.815-827 |
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Zusammenfassung: | 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. |
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ISSN: | 0001-6322 1432-0533 1432-0533 |
DOI: | 10.1007/s00401-023-02561-5 |