• 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 Adamek, Sandra 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, and Annie Huang.
• Division of Hematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, Peter Gilgan CRL,686 Bay Street, 17th Floor, 179712, Toronto, ON, M5G0A4, Canada.
• Acta Neuropathol. 2014 Aug 1; 128 (2): 291-303.

AbstractAmplification 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.

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