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


Journal Article

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.

Full Text

Cited Authors

  • Spence, T; Sin-Chan, P; Picard, D; Barszczyk, M; Hoss, K; Lu, M; Kim, S-K; Ra, Y-S; Nakamura, H; Fangusaro, J; Hwang, E; Kiehna, E; Toledano, H; Wang, Y; Shi, Q; Johnston, D; Michaud, J; La Spina, M; Buccoliero, AM; Adamek, D; Camelo-Piragua, S; Peter Collins, V; Jones, C; Kabbara, N; Jurdi, N; Varlet, P; Perry, A; Scharnhorst, D; Fan, X; Muraszko, KM; Eberhart, CG; Ng, H-K; Gururangan, S; Van Meter, T; Remke, M; Lafay-Cousin, L; Chan, JA; Sirachainan, N; Pomeroy, SL; Clifford, SC; Gajjar, A; Shago, M; Halliday, W; Taylor, MD; Grundy, R; Lau, CC; Phillips, J; Bouffet, E; Dirks, PB; Hawkins, CE; Huang, A

Published Date

  • August 2014

Published In

Volume / Issue

  • 128 / 2

Start / End Page

  • 291 - 303

PubMed ID

  • 24839957

Pubmed Central ID

  • 24839957

Electronic International Standard Serial Number (EISSN)

  • 1432-0533

International Standard Serial Number (ISSN)

  • 0001-6322

Digital Object Identifier (DOI)

  • 10.1007/s00401-014-1291-1


  • eng