New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

Abstract

SUMMARY Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)”, “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)”, and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)”, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

“…Other recent studies have shown that molecular profiling using genome-wide DNA methylation arrays can be a reliable and useful tool for aiding diagnostic classification of pediatric brain tumors. 13 However, the utility of DNA methylation profiling as a solitary tool is limited in that it does not allow assessment of germline alterations, somatic single nucleotide variants, or gene fusions. In select cases, there may be advantages of performing both DNA methylation profiling and targeted sequencing.…”

“…3), identical to that identified in the new molecular subtype of pediatric brain tumors entitled "CNS high-grade neuroepithelial tumor with BCOR alteration. " 13 Thus, a molecularly integrated diagnosis of CNS high-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication was made.…”

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

“…Molecular classification of cancer based on DNA methylomes has revolutionized the identification of tumor subclasses both in neurooncology [36][37][38][39] and in chronic lymphocytic leukemia 40,41 . Here we used an integrative approach and identified three clinically relevant JMML subgroups with distinct molecular genetic patterns (Fig.…”

Head and Neck Round Cell Sarcomas: A Comparative Clinicopathologic Analysis of 2 Molecular Subsets: Ewing and CIC-Rearranged Sarcomas

“…CIC, the human homologue of Drosophila capicua, encodes a transcriptional repressor with a highmobility group (HMG)-box containing DNA binding domain [28]. CIC gene abnormalities have been implicated in other tumors, either as loss of function mutations in oligodendrogliomas or as gene fusions in central nervous system primitive neuroectodermal tumors (PNET) and angiosarcomas [29][30][31][32]. DUX4 is normally expressed in germ cells and is epigenetically silenced in somatic differentiated tissues through CpG methylation [33].…”