BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young

Acta Neuropathol Commun. 2020 Aug 18;8(1):139. doi: 10.1186/s40478-020-01023-3.

Abstract

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

Keywords: BRAF V600E mutation; LAT1; Methionine PET; PLNTY.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Carbon Radioisotopes
  • Epilepsy, Temporal Lobe / etiology
  • Fluorodeoxyglucose F18
  • Humans
  • Male
  • Methionine
  • Mutation
  • Neoplasms, Neuroepithelial* / genetics
  • Neoplasms, Neuroepithelial* / metabolism
  • Neoplasms, Neuroepithelial* / pathology
  • Positron-Emission Tomography / methods
  • Proto-Oncogene Proteins B-raf / genetics*
  • Radiopharmaceuticals

Substances

  • Carbon Radioisotopes
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18
  • Methionine
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf