Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma.
Owen S ChapmanJens LuebeckSunita SridharIvy Tsz-Lo WongDeobrat DixitShanqing WangGino PrasadUtkrisht RajkumarMeghana S PagadalaJon D LarsonBritney Jiayu HeKing L HungJoshua T LangeSiavash R DehkordiSahaana ChandranMiriam AdamLing MorganSameena WaniAshutosh TiwariCaitlin GuccioneYingxi LinAditi DuttaYan Yuen LoEdwin JuarezJames T RobinsonAndrey KorshunovJohn-Edward A MichaelsYoon-Jae ChoDenise M MalickiNicole G CoufalMichael L LevyCharlotte HobbsRichard H ScheuermannJohn R CrawfordScott L PomeroyJeremy N RichXinlian ZhangHoward Y ChangJesse R DixonAnindya BagchiAniruddha J DeshpandeHannah CarterErnest FraenkelPaul S MischelRobert J Wechsler-ReyaVineet BafnaJill P MesirovLukas ChavezPublished in: Nature genetics (2023)
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.
Keyphrases
- copy number
- single cell
- mitochondrial dna
- genome wide
- gene expression
- end stage renal disease
- ejection fraction
- chronic kidney disease
- dna methylation
- newly diagnosed
- transcription factor
- prognostic factors
- crispr cas
- high resolution
- single molecule
- circulating tumor
- genome editing
- chronic pain
- pain management
- quantum dots
- real time pcr
- sensitive detection