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

Tara Spence, Patrick Sin-Chan, Daniel Picard, Mark Barszczyk, Katharina Hoss, Mei Lu, Seung Ki Kim, Young Shin Ra, Hideo Nakamura, Jason Fangusaro, Eugene Hwang, Erin Kiehna, Helen Toledano, Yin Wang, Qing Shi, Donna Johnston, Jean Michaud, Milena La Spina, Anna Maria Buccoliero, Dariusz AdamekSandra Camelo-Piragua, V. Peter Collins, Chris Jones, Nabil Kabbara, Nawaf Jurdi, Pascale Varlet, Arie Perry, David Scharnhorst, Xing Fan, Karin M. Muraszko, Charles G. Eberhart, Ho Keung Ng, Sridharan Gururangan, Timothy Van Meter, Marc Remke, Lucie Lafay-Cousin, Jennifer A. Chan, Nongnuch Sirachainan, Scott L. Pomeroy, Steven C. Clifford, Amar Gajjar, Mary Shago, William Halliday, Michael D. Taylor, Richard Grundy, Ching C. Lau, Joanna Phillips, Eric Bouffet, Peter B. Dirks, Cynthia E. Hawkins, Annie Huang

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)291-303
Number of pages13
JournalActa neuropathologica
Issue number2
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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