CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity

Acta Neuropathol. 2014 Aug;128(2):291-303. doi: 10.1007/s00401-014-1291-1. Epub 2014 May 20.

Abstract

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / therapy
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • DNA Methyltransferase 3B
  • Diagnosis, Differential
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Infant
  • Male
  • MicroRNAs / genetics*
  • Multigene Family
  • Neuroectodermal Tumors, Primitive / diagnosis
  • Neuroectodermal Tumors, Primitive / genetics*
  • Neuroectodermal Tumors, Primitive / metabolism*
  • Neuroectodermal Tumors, Primitive / therapy
  • RNA-Binding Proteins / metabolism*

Substances

  • LIN28B protein, human
  • Lin28A protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • DNA (Cytosine-5-)-Methyltransferases