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

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 GuccioneYingxi 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

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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.

Original language	English (US)
Pages (from-to)	2189-2199
Number of pages	11
Journal	Nature genetics
Volume	55
Issue number	12
DOIs	https://doi.org/10.1038/s41588-023-01551-3
State	Published - Dec 2023

ASJC Scopus subject areas

Genetics

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Chapman, O. S., Luebeck, J., Sridhar, S., Wong, I. T. L., Dixit, D., Wang, S., Prasad, G., Rajkumar, U., Pagadala, M. S., Larson, J. D., He, B. J., Hung, K. L., Lange, J. T., Dehkordi, S. R., Chandran, S., Adam, M., Morgan, L., Wani, S., Tiwari, A., ... Chavez, L. (2023). Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma. Nature genetics, 55(12), 2189-2199. https://doi.org/10.1038/s41588-023-01551-3

Chapman, OS, Luebeck, J, Sridhar, S, Wong, ITL, Dixit, D, Wang, S, Prasad, G, Rajkumar, U, Pagadala, MS, Larson, JD, He, BJ, Hung, KL, Lange, JT, Dehkordi, SR, Chandran, S, Adam, M, Morgan, L, Wani, S, Tiwari, A, Guccione, C, Lin, Y, Dutta, A, Lo, YY, Juarez, E, Robinson, JT, Korshunov, A, Michaels, JEA, Cho, YJ, Malicki, DM, Coufal, NG, Levy, ML, Hobbs, C, Scheuermann, RH, Crawford, JR, Pomeroy, SL, Rich, JN, Zhang, X, Chang, HY, Dixon, JR, Bagchi, A, Deshpande, AJ, Carter, H, Fraenkel, E, Mischel, PS, Wechsler-Reya, RJ, Bafna, V, Mesirov, JP & Chavez, L 2023, 'Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma', Nature genetics, vol. 55, no. 12, pp. 2189-2199. https://doi.org/10.1038/s41588-023-01551-3

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title = "Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma",

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 {\textquoteleft}enhancer rewiring{\textquoteright} 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.",

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

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year = "2023",

month = dec,

doi = "10.1038/s41588-023-01551-3",

language = "English (US)",

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AU - Chapman, Owen S.

AU - Luebeck, Jens

AU - Sridhar, Sunita

AU - Wong, Ivy Tsz Lo

AU - Dixit, Deobrat

AU - Wang, Shanqing

AU - Prasad, Gino

AU - Rajkumar, Utkrisht

AU - Pagadala, Meghana S.

AU - Larson, Jon D.

AU - He, Britney Jiayu

AU - Hung, King L.

AU - Lange, Joshua T.

AU - Dehkordi, Siavash R.

AU - Chandran, Sahaana

AU - Adam, Miriam

AU - Morgan, Ling

AU - Wani, Sameena

AU - Tiwari, Ashutosh

AU - Guccione, Caitlin

AU - Lin, Yingxi

AU - Dutta, Aditi

AU - Lo, Yan Yuen

AU - Juarez, Edwin

AU - Robinson, James T.

AU - Korshunov, Andrey

AU - Michaels, John Edward A.

AU - Cho, Yoon Jae

AU - Malicki, Denise M.

AU - Coufal, Nicole G.

AU - Levy, Michael L.

AU - Hobbs, Charlotte

AU - Scheuermann, Richard H.

AU - Crawford, John R.

AU - Pomeroy, Scott L.

AU - Rich, Jeremy N.

AU - Zhang, Xinlian

AU - Chang, Howard Y.

AU - Dixon, Jesse R.

AU - Bagchi, Anindya

AU - Deshpande, Aniruddha J.

AU - Carter, Hannah

AU - Fraenkel, Ernest

AU - Mischel, Paul S.

AU - Wechsler-Reya, Robert J.

AU - Bafna, Vineet

AU - Mesirov, Jill P.

AU - Chavez, Lukas

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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JO - Nature genetics

JF - Nature genetics

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Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma

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