Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

Owen S Chapman; Jens Luebeck; Sunita Sridhar; Ivy Tsz-Lo Wong; Deobrat Dixit; Shanqing Wang; Gino Prasad; Utkrisht Rajkumar; Meghana S Pagadala; Jon D Larson; Britney Jiayu He; King L Hung; Joshua T Lange; Siavash R Dehkordi; Sahaana Chandran; Miriam Adam; Ling Morgan; Sameena Wani; Ashutosh Tiwari; Caitlin Guccione; Yingxi Lin; Aditi Dutta; Yan Yuen Lo; Edwin Juarez; James T Robinson; Andrey Korshunov; John-Edward A Michaels; Yoon-Jae Cho; Denise M Malicki; Nicole G Coufal; Michael L Levy; Charlotte Hobbs; Richard H Scheuermann; John R Crawford; Scott L Pomeroy; Jeremy N Rich; Xinlian Zhang; Howard Y Chang; Jesse R Dixon; Anindya Bagchi; Aniruddha J Deshpande; Hannah Carter; Ernest Fraenkel; Paul S Mischel; Robert J Wechsler-Reya; Vineet Bafna; Jill P Mesirov; Lukas Chavez

doi:10.1038/s41588-023-01551-3

Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

Nat Genet. 2023 Dec;55(12):2189-2199. doi: 10.1038/s41588-023-01551-3. Epub 2023 Nov 9.

Authors

Owen S Chapman^{1

2

3}, Jens Luebeck^{1

4}, Sunita Sridhar^{2

5}, Ivy Tsz-Lo Wong^{6

7}, Deobrat Dixit^{3

8}, Shanqing Wang⁴, Gino Prasad⁴, Utkrisht Rajkumar⁴, Meghana S Pagadala^{9

10}, Jon D Larson³, Britney Jiayu He¹¹, King L Hung¹¹, Joshua T Lange^{6

7}, Siavash R Dehkordi⁴, Sahaana Chandran¹², Miriam Adam¹³, Ling Morgan², Sameena Wani³, Ashutosh Tiwari³, Caitlin Guccione^{1

2}, Yingxi Lin⁴, Aditi Dutta⁴, Yan Yuen Lo^{3

14}, Edwin Juarez², James T Robinson², Andrey Korshunov¹⁵, John-Edward A Michaels¹⁶, Yoon-Jae Cho¹⁶, Denise M Malicki¹⁷, Nicole G Coufal⁵, Michael L Levy¹⁷, Charlotte Hobbs¹⁴, Richard H Scheuermann^{18

19}, John R Crawford²⁰, Scott L Pomeroy^{21

22

23}, Jeremy N Rich^{24

25}, Xinlian Zhang²⁶, Howard Y Chang^{11

27

28}, Jesse R Dixon¹², Anindya Bagchi³, Aniruddha J Deshpande³, Hannah Carter^{2

29}, Ernest Fraenkel^{13

21}, Paul S Mischel^{6

7}, Robert J Wechsler-Reya^{3

8}, Vineet Bafna^{4

29}, Jill P Mesirov^{2

29}, Lukas Chavez^{30

31

32

33}

Affiliations

¹ Bioinformatics and Systems Biology Graduate Program, University of California San Diego, San Diego, CA, USA.
² Department of Medicine, University of California San Diego, San Diego, CA, USA.
³ Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA.
⁴ Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA.
⁵ Department of Pediatrics, UC San Diego and Rady Children's Hospital, San Diego, CA, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁸ Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
⁹ Medical Scientist Training Program, University of California San Diego, San Diego, CA, USA.
¹⁰ Biomedical Sciences Graduate Program, University of California San Diego, San Diego, CA, USA.
¹¹ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
¹² Salk Institute for Biological Studies, La Jolla, CA, USA.
¹³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Rady Children's Institute for Genomic Medicine, Rady Children's Hospital and Healthcare Center, San Diego, CA, USA.
¹⁵ Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 280, Heidelberg, Germany.
¹⁶ Papé Pediatric Research Institute, Department of Pediatrics and Knight Cancer Insitute, Oregon Health and Sciences University, Portland, OR, USA.
¹⁷ Division of Pathology, UC San Diego and Rady Children's Hospital, San Diego, CA, USA.
¹⁸ J. Craig Venter Institute, La Jolla, CA, USA.
¹⁹ Department of Pathology, University of California San Diego, San Diego, CA, USA.
²⁰ Department of Pediatrics, University of California Irvine and Children's Hospital Orange County, Irvine, CA, USA.
²¹ Eli and Edythe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²² Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
²³ Harvard Medical School, Boston, MA, USA.
²⁴ UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
²⁵ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
²⁶ Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA, USA.
²⁷ Department of Genetics, Stanford University, Stanford, CA, USA.
²⁸ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁹ Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
³⁰ Department of Medicine, University of California San Diego, San Diego, CA, USA. lchavez@sbpdiscovery.org.
³¹ Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA. lchavez@sbpdiscovery.org.
³² Rady Children's Institute for Genomic Medicine, Rady Children's Hospital and Healthcare Center, San Diego, CA, USA. lchavez@sbpdiscovery.org.
³³ Moores Cancer Center, University of California San Diego, San Diego, CA, USA. lchavez@sbpdiscovery.org.

Abstract

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.

MeSH terms

Cerebellar Neoplasms* / genetics
DNA, Circular
Humans
Medulloblastoma* / genetics
Neoplasms* / genetics
Oncogenes
Retrospective Studies

Substances

DNA, Circular

Abstract

MeSH terms

Substances

Grants and funding