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

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.

DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

“…Notably, we and others have identified a subtype of CNS-PNETs (which we call Group 1 CNS-PNETs) distinguished by hallmark genomic amplification of the embryonic stem cell (ES)-enriched C19MC oncogenic miRNA cluster and histological features reminiscent of very early neural differentiation [3,4]. Significantly in recent studies, we observed C19MC amplification in CNS-PNETs with different histologic diagnostic labels, including ETANTRs, ependymoblastoma and medulloepithelioma, originating in various CNS locations [5,6]. These Group 1 tumors collectively comprise~25% of all CNS-PNETs arising in very young children (> 80% are < 4 years old), and are distinctly lethal tumors with characteristic rapid disease tempo.…”

“…Mechanisms that drive and underlie hypermethylator phenotype in specific brain tumors remain to be elucidated; however, studies in malignant glioma cells show 5-AzadCyD treatment promotes differentiation, reduces global DNA methylation and results in reactivation of the p53 tumor suppressor pathway [15]. Significantly, we have observed that cell lines derived from C19MC-associated Group 1 CNS-PNETs, which express high levels of DNMT3B, are also remarkably sensitive to treatment with 5-AzaC, as well as Vorinostat, an HDAC inhibitor [5]. These data provide the first functional evidence that targeting epigenomic modifiers represent promising, novel therapeutic approaches for these recalcitrant tumors (Figure 2).…”

“…Notably, recent studies demonstrate C19MC-associated Group 1 tumors with various histologic labels and anatomic location exhibit a common transcriptional and epigenomic signature, distinct from that of other CNS-PNETs, thus indicating these tumors comprise a common molecular disease [5,6]. Consistent with their distinctly primitive histology, transcriptional signatures of C19MC-associated tumors show most remarkable enrichment of pluripotency and early neural differentiation genes.…”

“…Most notably, pluripotency gene LIN28, which is known to modulate cellular growth and differentiation via regulation of the highly conserved let-7 family of miRNAs and the PI3K-mTOR signaling pathway [7], is one of the most highly expressed genes in Group 1 tumors. Indeed, in vitro studies demonstrate preservation of the LIN28-PI3K-mTOR axis and sensitivity to Rapamycin, an mTOR inhibitor, in two independent Group 1 cell lines [5,8].…”

“…Genetic alterations of DNMTs remain to be identified in brain tumors; however, substantial evidence suggests deregulation of DNMTs that function in maintaining and establishing de novo DNA methylation also contributes to pediatric brain tumor pathogenesis. Subgroups of CNS-PNETs exhibit highly distinct DNA methylation patterns thus suggesting epigenomic mechanisms may also be important in these embryonal tumors [5,6]. Indeed, recent RNA-sequencing studies revealed recurrent gene fusions of C19MC with TTYH1, a developmentally restricted chloride channel gene, associated with very high expression of some C19MC miRNAs and a neural-specific DNMT3B isoform in Group 1 tumors, due to C19MC-mediated targeting of RBL2, a transcriptional repressor of DNMT3B [14].…”