Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course

Sci Rep. 2020 Jan 9;10(1):96. doi: 10.1038/s41598-019-56146-y.

Abstract

Long-term epilepsy-associated tumors (LEATs) represent mostly benign brain tumors associated with drug-resistant epilepsy. The aim of the study was to investigate the specific transcriptional signatures of those tumors and characterize their underlying oncogenic drivers. A cluster analysis of 65 transcriptome profiles from three independent datasets resulted in four distinct transcriptional subgroups. The first subgroup revealed transcriptional activation of STAT3 and TGF-signaling pathways and contained predominantly dysembryoplastic neuroepithelial tumors (DNTs). The second subgroup was characterized by alterations in the MAPK-pathway and up-stream cascades including FGFR and EGFR-mediated signaling. This tumor cluster exclusively contained neoplasms with somatic BRAFV600E mutations and abundance of gangliogliomas (GGs) with a significantly higher recurrence rate (42%). This finding was validated by examining recurrent tumors from the local database exhibiting BRAFV600E in 90% of the cases. The third cluster included younger patients with neuropathologically diagnosed GGs and abundance of the NOTCH- and mTOR-signaling pathways. The transcript signature of the fourth cluster (including both DNTs and GGs) was related to impaired neural function. Our analysis suggests distinct oncological pathomechanisms in long-term epilepsy-associated tumors. Transcriptional activation of MAPK-pathway and BRAFV600E mutation are associated with an increased risk for tumor recurrence and malignant progression, therefore the treatment of these tumors should integrate both epileptological and oncological aspects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / etiology*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Child
  • Epilepsy / complications*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / etiology*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Young Adult

Substances

  • Biomarkers, Tumor