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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1291-1) contains supplementary material, which is available to authorized users.
Highlights
Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) are a heterogeneous group of pediatric neoplasms composed of poorly differentiated neuroepithelial cells with varying degrees of divergent neural, astrocytic and ependymal differentiation
Of the 54 group 1 CNSPNETs examined for detailed histopathologic correlates (Table 1 and Supplemental Table 2), 33 were previously reported [13, 17]; and 21 additional tumors with a diagnosis of CNS-PNET, ETANTR or embryonal tumor with multilayered rosettes (ETMR), MEP and EPB were collected for this study
We identified three transcriptional classes of CNS-PNETs arising in the cerebral hemispheres
Summary
Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) are a heterogeneous group of pediatric neoplasms composed of poorly differentiated neuroepithelial cells with varying degrees of divergent neural, astrocytic and ependymal differentiation. In 2000, Eberhart et al [4] described a new CNS-PNET variant arising primarily in infancy, which displayed histological features of both neuroblastoma and EPB, and were distinguished by the presence of true and pseudo-rosettes on a background of abundant neuropil. These tumors, termed ‘embryonal tumors with abundant neuropil and true rosettes’ (ETANTRs), correlated with very poor patient prognosis with a mortality rate of 76 % and a median survival of 9 months [1, 5, 21]. Subsequent studies demonstrated that upregulation of the RNA-binding pluripotency gene, LIN28 [11, 17], correlated closely with C19MC amplification suggesting that LIN28 may represent an attractive immunodiagnostic marker for this distinct molecular sub-group of
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