Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma
Menée à l'aide de lignées cellulaires, de modèles murins et de données de séquençage du génome entier portant sur 481 médulloblastomes issus de 465 patients, cette étude analyse la fréquence et la diversité des ADN extrachromosomiques circulaires puis met en évidence leur rôle dans l'hétérogénéité intratumorale
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.
Nature Genetics , article en libre accès, 2023