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Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery.

ABSTRACT: Malformations of cortical development (MCD) comprise a broad spectrum of developmental brain abnormalities. Patients presenting with MCDs often suffer from drug-resistant focal epilepsy, and some become candidates for epilepsy surgery. Their likelihood of achieving freedom from seizures, however, remains uncertain, and depends in a major part on the underlying pathology. Tissue samples obtained in epilepsy surgery form the basis of definite histopathological diagnosis; however, new molecular genetic methods have not yet been implemented in diagnostic processes for MCD cases. Furthermore, it has not been completely understood how the underlying pathology affects patients' outcomes after epilepsy surgery. We performed a systematic literature review of studies describing both histopathological and molecular genetic findings in MCD, along with studies on epilepsy surgery outcomes. We aimed to correlate the genetic causes with the underlying morphological abnormalities in focal cortical malformations and to stress the importance of the underlying biology for patient management and counseling. From the summarized findings of multiple authors, it is obvious that MCD may have a diverse genetic background despite a similar or even identical histopathological picture. Even though most of their molecular genetic findings converge on various levels of the PI3K/AKT/mTOR pathway, the exact mechanisms underlying MCD formation have not yet been completely described or indeed how this pathway generates a diverse range of histological abnormalities. Based on our findings, we therefore propose that all patients diagnosed and operated for drug-resistant epilepsy should have an integrated molecular and pathological diagnosis similar to the current practice in brain tumor diagnostic processes that might lead to more accurate diagnosis and effective stratification of patients undergoing epilepsy surgery.

SUBMITTER: Benova B

PROVIDER: S-EPMC8028510 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the genetic landscape and genotype-phenotype correlation of this enigmatic and often difficult-to-classify epilepsy-associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next-generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)-like tumor component, were separately studied. A mean post-surgical follow-up time-period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R, IRS2 copy number gain (CNG) and a KIAA1549-BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG-like features. Follow-up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki-67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular-genetic differentiation from the cohort of low-grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio-neuronal GG variants.

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Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery.

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