Cross-species genomics matches driver mutations and cell compartments to model ependymoma

摘要: Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and cellular origins most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched candidate cells origin generate accurate disease models. First, we identified human ependymoma, a form neural tumour arises throughout central nervous system (CNS). Subgroup-specific included amplifications homozygous deletions genes not yet implicated in ependymoma. To select compartments likely give rise transcriptomes tumours those mouse stem (NSCs), isolated from different regions CNS at developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a b). The transcriptome supratentorial ependymomas amplified EPHB2 INK4A/ARF only embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation Ephb2 signalling these, other, NSCs generated first model which is highly penetrant accurately models histology one subgroup tumour. Further, comparative analysis revealed selective deregulation expression copy number control synaptogenesis, pinpointing disruption pathway as critical event production ependymoma subgroup. Our data demonstrate power cross-species genomics meticulously match subgroup-specific driver mutations interrogate subgroups.