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.