Bio


I am a physician scientist trained in pathology and cancer biology. My lab has made a series of discoveries published in Nature, Science, and Nature Genetics, that have identified a central role for ecDNA (extrachromosomal DNA) in cancer development, progression, accelerated tumor evolution and drug resistance. These findings have provided a new understanding of the fundamental mechanisms of oncogene amplification and the spatial organization of altered tumor genomes, launching a new area of cancer research that links circular architecture with tumor pathogenesis. I lead Team eDyNAmiC, which was awarded one of the $25M Cancer Grand Challenges Awards from CRUK and the National Cancer Institute, to tackle the extrachromosomal DNA grand challenge. My lab has also uncovered metabolic co-dependencies that are downstream consequences of oncogene amplification. These include a central role for altered biochemical mechanisms that regulate oncogene copy number and function. These discoveries have resulted in new understandings of some of the fundamental processes by which oncogene amplification drives cancer progression and drug resistance and pointed that way towards new treatments that are being developed.

Academic Appointments


Administrative Appointments


  • Professor of Pathology, Stanford University School of Medicine (2021 - Present)
  • Vice Chair for Research, Department of Pathology, Stanford University School of Medicine (2021 - Present)
  • Institute Scholar, ChEM-H, Stanford University (2021 - Present)

Honors & Awards


  • Ernst W. Bertner Memorial Award for Distinguished Contributions to Cancer Research, MD Anderson (2023)
  • Member, National Academy of Medicine
  • Elected Fellow, American Association for the Advancement of Science (2015)
  • Elected Member, American Association of Physicians (2012-present)
  • President, American Society for Clinical Investigation (2010-2011)
  • Elected Member, American Society for Clinical Investigation (2007-present)
  • American's Top Doctors for Cancer, Castle & Connelly (2006-2021)
  • Americas Top Doctors for Pathology, Castle & Connelly (2006-2021)
  • Farber Award for Brain Cancer Research, American Association of Neurological Surgeons and the Society for Neuro-Oncology (2004)
  • Pfizer New Faculty Scholar, Pfizer (1996)
  • Alpha Omega Alpha, AOA (1991)

Boards, Advisory Committees, Professional Organizations


  • Co-Founder and Chair of Scientific Advisory Board, Boundless Bio, Inc. (2018 - Present)

Professional Education


  • Post-Doctoral Fellowship, HHMI-UCSF (mentored by Dr. Louis Reichardt), Molecular Neuroscience (1998)
  • Residency, UCLA, Pathology and Neuropathology (1996)
  • M.D., Cornell University Medical College (Weill Cornell), Medicine (1991)
  • B.A., University of Pennsylvania, Philosphy (1984)

Current Research and Scholarly Interests


Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA don’t follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments, at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumor growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat and cancer patients whose tumours harbour ecDNA have markedly shorter survival.

Despite being first seen over fifty years, ago, and prescient work on its potential importance, the scale, scope, and impact of ecDNA was not well understood. In fact, it was thought to be a rare event of unknown significance. The application of powerful new, integrative molecular approaches has shown us, that ecDNAs are present in nearly half of all human cancer types and at likely in at least a quarter of all cancer patients and they have taught us that ecDNA is indeed, one of the most urgent problems facing patients with cancer, challenging the success of the targeted therapy approaches, and a problem that is certainly worthy of its nomination as a Cancer Grant Challenge. Currently, the collective current understanding of how ecDNA form, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted, are lacking. Can we identify actionable co-dependency pathways that are generated by ecDNA amplification? These are the areas of research focus of research in my laboratory.

We are very collaborative and interactive, with many colleagues around the world. We work very closely with Professor Howard Chang at Stanford, as well as with many other new Stanford colleagues. I have recently joined the faculty of Stanford University as a Professor and Vice Chair for Research for the Department of Pathology, and as an Institute Scholar in ChEM-H, where my lab is based. I am committed to actively contributing not only to the science and its translation for benefit to patients, but also to mentoring trainees at all levels, and helping colleagues, including junior colleagues, develop the skills necessary to navigate the complex landscape of translating science into medicines that will help patients.

2023-24 Courses


Stanford Advisees


All Publications


  • Oncogenic extrachromosomal DNA identification using whole-genome sequencing from formalin-fixed glioblastomas. Annals of oncology : official journal of the European Society for Medical Oncology Noorani, I., Luebeck, J., Rowan, A., Gronroos, E., Barbe, V., Fabian, M., Nicoll, J., Boche, D., Bafna, V., Mischel, P. S., Swanton, C. 2024

    View details for DOI 10.1016/j.annonc.2024.03.008

    View details for PubMedID 38555024

  • Extrachromosomal DNA in cancer. Nature reviews. Cancer Yan, X., Mischel, P., Chang, H. 2024

    Abstract

    Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesisthat is identified in most cancer types and isassociated with poor outcomes. When it wasdiscovered over 60years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer. The non-chromosomal inheritance of ecDNA during cell division results in high oncogene copy number, intra-tumoural genetic heterogeneity and rapid tumour evolution thatcontributes to treatment resistance and shorter patient survival. In addition, the circular architecture of ecDNA results in altered patterns of gene regulation that drive elevated oncogene expression, potentially enabling the remodelling of tumour genomes. The generation of clusters of ecDNAs, termed ecDNA hubs, results in interactions between enhancers and promoters in trans, yielding a new paradigm in oncogenic transcription. In this Review, we highlight the rapid advancements in ecDNA research, providing new insights into ecDNA biogenesis, maintenance andtranscription and itsrole in promoting tumour heterogeneity. To conclude, we delve into a set of unanswered questions whose answers will pave the way for the development of ecDNA targeted therapeutic approaches.

    View details for DOI 10.1038/s41568-024-00669-8

    View details for PubMedID 38409389

  • CoRAL accurately resolves extrachromosomal DNA genome structures with long-read sequencing. bioRxiv : the preprint server for biology Zhu, K., Jones, M. G., Luebeck, J., Bu, X., Yi, H., Hung, K. L., Wong, I. T., Zhang, S., Mischel, P. S., Chang, H. Y., Bafna, V. 2024

    Abstract

    Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring in approximately 15% of early stage cancers and 30% of late-stage cancers. EcDNAs drive tumor formation, evolution, and drug resistance by dynamically modulating oncogene copy-number and rewiring gene-regulatory networks. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Paired-end short-read (Illumina) sequencing and mapping have been utilized to represent ecDNA amplifications using a breakpoint graph, where the inferred architecture of ecDNA is encoded as a cycle in the graph. Traversals of breakpoint graph have been used to successfully predict ecDNA presence in cancer samples. However, short-read technologies are intrinsically limited in the identification of breakpoints, phasing together of complex rearrangements and internal duplications, and deconvolution of cell-to-cell heterogeneity of ecDNA structures. Long-read technologies, such as from Oxford Nanopore Technologies, have the potential to improve inference as the longer reads are better at mapping structural variants and are more likely to span rearranged or duplicated regions. Here, we propose CoRAL (Complete Reconstruction of Amplifications with Long reads), for reconstructing ecDNA architectures using long-read data. CoRAL reconstructs likely cyclic architectures using quadratic programming that simultaneously optimizes parsimony of reconstruction, explained copy number, and consistency of long-read mapping. CoRAL substantially improves reconstructions in extensive simulations and 9 datasets from previously-characterized cell-lines as compared to previous short-read-based tools. As long-read usage becomes wide-spread, we anticipate that CoRAL will be a valuable tool for profiling the landscape and evolution of focal amplifications in tumors. Availability: https://github.com/AmpliconSuite/CoRAL.

    View details for DOI 10.1101/2024.02.15.580594

    View details for PubMedID 38405779

  • Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change. bioRxiv : the preprint server for biology Dehkordi, S. R., Wong, I. T., Ni, J., Luebeck, J., Zhu, K., Prasad, G., Krockenberger, L., Xu, G., Chowdhury, B., Rajkumar, U., Caplin, A., Muliaditan, D., Coruh, C., Jin, Q., Turner, K., Teo, S. X., Pang, A. W., Alexandrov, L. B., Chua, C. E., Furnari, F. B., Paulson, T. G., Law, J. A., Chang, H. Y., Yue, F., DasGupta, R., Zhao, J., Mischel, P. S., Bafna, V. 2023

    Abstract

    Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.

    View details for DOI 10.1101/2023.12.12.571349

    View details for PubMedID 38168210

  • Cancer in 2023 CANCER DISCOVERY Greenberg, P. D., Abbruzzese, J. L., Cohen, E. W., Domcheck, S. M., Doubeni, C. A., Elkins, I., Formenti, S. C., Foti, M., Fuchs, T. J., Kucharczuk, J. C., Majeti, R., Mischel, P., Mucci, L. A., Sharma, P., Simon, M. A., Sweet-Cordero, A., Thanarajasingam, G., AACR Canc Progress Report 2023 2023; 13 (12): 2510-2514
  • Circular extrachromosomal DNA promotes tumor heterogeneity in high-risk medulloblastoma. Nature genetics Chapman, O. S., Luebeck, J., Sridhar, S., Wong, I. T., 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., Guccione, C., Lin, Y., Dutta, A., Lo, Y. Y., Juarez, E., Robinson, J. T., Korshunov, A., Michaels, J. A., Cho, Y. J., Malicki, D. M., Coufal, N. G., Levy, M. L., Hobbs, C., Scheuermann, R. H., Crawford, J. R., Pomeroy, S. L., Rich, J. N., Zhang, X., Chang, H. Y., Dixon, J. R., Bagchi, A., Deshpande, A. J., Carter, H., Fraenkel, E., Mischel, P. S., Wechsler-Reya, R. J., Bafna, V., Mesirov, J. P., Chavez, L. 2023

    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.

    View details for DOI 10.1038/s41588-023-01551-3

    View details for PubMedID 37945900

    View details for PubMedCentralID 5334176

  • A Year of Advances in Precision Therapy for Blood Cancers BLOOD CANCER DISCOVERY Greenberg, P. D., Abbruzzese, J. L., Cohen, E. W., Domcheck, S. M., Doubeni, C. A., Elkins, I., Formenti, S. C., Foti, M., Fuchs, T. J., Kucharczuk, J. C., Majeti, R., Mischel, P., Mucci, L. A., Sharma, P., Simon, M. A., Sweet-Cordero, A., Thanarajasingam, G., AACR Canc Progress Report 2023 Ste 2023; 4 (6): 423-426

    Abstract

    Recent advances in precision therapies of blood cancers are highlighted here, adapted from the 13th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to U.S. Congress and the public.

    View details for DOI 10.1158/2643-3230.BCD-23-0193

    View details for Web of Science ID 001158361700009

    View details for PubMedID 37847742

    View details for PubMedCentralID PMC10618723

  • A RANDOMIZED WINDOW OF OPPORTUNITY TRIAL WITH DOSE ESCALATION TO EVALUATE FLUOXETINE AND TEMOZOLOMIDE IN GLIOMA Singh, K., Railton, C., Hotchkiss, K., Herndon, J., Peters, K., Friedman, H., Desjardins, A., Ashley, D., Johnson, M. O., Patel, A., Friedman, A., Lim, M., Fecci, P., Piccioni, D., McGranahan, T., Nagpal, S., Sulman, E., Mischel, P., Khasraw, M. OXFORD UNIV PRESS INC. 2023
  • Disparate pathways for extrachromosomal DNA biogenesis and genomic DNA repair. bioRxiv : the preprint server for biology Rose, J. C., Wong, I. T., Daniel, B., Jones, M. G., Yost, K. E., Hung, K. L., Curtis, E. J., Mischel, P. S., Chang, H. Y. 2023

    Abstract

    Oncogene amplification on extrachromosomal DNA (ecDNA) is a pervasive driver event in cancer, yet our understanding of how ecDNA forms is limited. Here, we couple a CRISPR-based method for induction of ecDNA with extensive characterization of newly formed ecDNA to examine ecDNA biogenesis. We find that DNA circularization is efficient, irrespective of 3D genome context, with formation of a 1 Mb and 1.8 Mb ecDNA both reaching 15%. We show non-homologous end joining and microhomology mediated end joining both contribute to ecDNA formation, while inhibition of DNA-PKcs and ATM have opposing impacts on ecDNA formation. EcDNA and the corresponding chromosomal excision scar form at significantly different rates and respond differently to DNA-PKcs and ATM inhibition. Taken together, our results support a model of ecDNA formation in which double strand break ends dissociate from their legitimate ligation partners prior to joining of illegitimate ends to form the ecDNA and excision scar.

    View details for DOI 10.1101/2023.10.22.563489

    View details for PubMedID 37961138

  • Coordinated inheritance of extrachromosomal DNA species in human cancer cells. bioRxiv : the preprint server for biology Hung, K. L., Jones, M. G., Wong, I. T., Lange, J. T., Luebeck, J., Scanu, E., He, B. J., Brückner, L., Li, R., González, R. C., Schmargon, R., Dörr, J. R., Belk, J. A., Bafna, V., Werner, B., Huang, W., Henssen, A. G., Mischel, P. S., Chang, H. Y. 2023

    Abstract

    The chromosomal theory of inheritance has dominated human genetics, including cancer genetics. Genes on the same chromosome segregate together while genes on different chromosomes assort independently, providing a fundamental tenet of Mendelian inheritance. Extrachromosomal DNA (ecDNA) is a frequent event in cancer that drives oncogene amplification, dysregulated gene expression and intratumoral heterogeneity, including through random segregation during cell division. Distinct ecDNA sequences, herein termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells. However, how multiple ecDNA species within a tumor cell are assorted and maintained across somatic cell generations to drive cancer cell evolution is not known. Here we show that cooperative ecDNA species can be coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. EcDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy number gains in multiple ecDNA species prior to any selection. Computational modeling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Finally, we show that coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.

    View details for DOI 10.1101/2023.07.18.549597

    View details for PubMedID 37503111

    View details for PubMedCentralID PMC10371175

  • Epigenetic dysregulation from chromosomal transit in micronuclei. Nature Agustinus, A. S., Al-Rawi, D., Dameracharla, B., Raviram, R., Jones, B. S., Stransky, S., Scipioni, L., Luebeck, J., Di Bona, M., Norkunaite, D., Myers, R. M., Duran, M., Choi, S., Weigelt, B., Yomtoubian, S., McPherson, A., Toufektchan, E., Keuper, K., Mischel, P. S., Mittal, V., Shah, S. P., Maciejowski, J., Storchova, Z., Gratton, E., Ly, P., Landau, D., Bakhoum, M. F., Koche, R. P., Sidoli, S., Bafna, V., David, Y., Bakhoum, S. F. 2023

    Abstract

    Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

    View details for DOI 10.1038/s41586-023-06084-7

    View details for PubMedID 37286593

    View details for PubMedCentralID 3894624

  • Integrated analysis of single-cell chromatin state and transcriptome identified common vulnerability despite glioblastoma heterogeneity. Proceedings of the National Academy of Sciences of the United States of America Raviram, R., Raman, A., Preissl, S., Ning, J., Wu, S., Koga, T., Zhang, K., Brennan, C. W., Zhu, C., Luebeck, J., Van Deynze, K., Han, J. Y., Hou, X., Ye, Z., Mischel, A. K., Li, Y. E., Fang, R., Baback, T., Mugford, J., Han, C. Z., Glass, C. K., Barr, C. L., Mischel, P. S., Bafna, V., Escoubet, L., Ren, B., Chen, C. C. 2023; 120 (20): e2210991120

    Abstract

    In 2021, the World Health Organization reclassified glioblastoma, the most common form of adult brain cancer, into isocitrate dehydrogenase (IDH)-wild-type glioblastomas and grade IV IDH mutant (G4 IDHm) astrocytomas. For both tumor types, intratumoral heterogeneity is a key contributor to therapeutic failure. To better define this heterogeneity, genome-wide chromatin accessibility and transcription profiles of clinical samples of glioblastomas and G4 IDHm astrocytomas were analyzed at single-cell resolution. These profiles afforded resolution of intratumoral genetic heterogeneity, including delineation of cell-to-cell variations in distinct cell states, focal gene amplifications, as well as extrachromosomal circular DNAs. Despite differences in IDH mutation status and significant intratumoral heterogeneity, the profiled tumor cells shared a common chromatin structure defined by open regions enriched for nuclear factor 1 transcription factors (NFIA and NFIB). Silencing of NFIA or NFIB suppressed in vitro and in vivo growths of patient-derived glioblastomas and G4 IDHm astrocytoma models. These findings suggest that despite distinct genotypes and cell states, glioblastoma/G4 astrocytoma cells share dependency on core transcriptional programs, yielding an attractive platform for addressing therapeutic challenges associated with intratumoral heterogeneity.

    View details for DOI 10.1073/pnas.2210991120

    View details for PubMedID 37155843

  • Transcriptional immune suppression and upregulation of double stranded DNA damage and repair repertoires in ecDNA-containing tumors. bioRxiv : the preprint server for biology Lin, M. S., Jo, S. Y., Luebeck, J., Chang, H. Y., Wu, S., Mischel, P. S., Bafna, V. 2023

    Abstract

    Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here we show that ecDNA containing tumors impact four major biological processes. Specifically, ecDNA containing tumors upregulate DNA damage and repair, cell cycle control, and mitotic processes, but downregulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA containing tumors, shedding light on molecular processes that give rise to their development and progression.

    View details for DOI 10.1101/2023.04.24.537925

    View details for PubMedID 37162993

    View details for PubMedCentralID PMC10168239

  • Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus. Nature Luebeck, J., Ng, A. W., Galipeau, P. C., Li, X., Sanchez, C. A., Katz-Summercorn, A. C., Kim, H., Jammula, S., He, Y., Lippman, S. M., Verhaak, R. G., Maley, C. C., Alexandrov, L. B., Reid, B. J., Fitzgerald, R. C., Paulson, T. G., Chang, H. Y., Wu, S., Bafna, V., Mischel, P. S. 2023

    Abstract

    Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal ademocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

    View details for DOI 10.1038/s41586-023-05937-5

    View details for PubMedID 37046089

    View details for PubMedCentralID 5334176

  • Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH. Nature genetics Hung, K. L., Luebeck, J., Dehkordi, S. R., Colon, C. I., Li, R., Wong, I. T., Coruh, C., Dharanipragada, P., Lomeli, S. H., Weiser, N. E., Moriceau, G., Zhang, X., Bailey, C., Houlahan, K. E., Yang, W., Gonzalez, R. C., Swanton, C., Curtis, C., Jamal-Hanjani, M., Henssen, A. G., Law, J. A., Greenleaf, W. J., Lo, R. S., Mischel, P. S., Bafna, V., Chang, H. Y. 2022

    Abstract

    Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but is challenging to analyze. Here, we adapt CRISPR-CATCH, in vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA, previously developed for bacterial chromosome segments, to isolate megabase-sized human ecDNAs. We demonstrate strong enrichment of ecDNA molecules containing EGFR, FGFR2 and MYC from human cancer cells and NRAS ecDNA from human metastatic melanoma with acquired therapeutic resistance. Targeted enrichment of ecDNA versus chromosomal DNA enabled phasing of genetic variants, identified the presence of an EGFRvIII mutation exclusively on ecDNAs and supported an excision model of ecDNA genesis in a glioblastoma model. CRISPR-CATCH followed by nanopore sequencing enabled single-molecule ecDNA methylation profiling and revealed hypomethylation of the EGFR promoter on ecDNAs. We distinguished heterogeneous ecDNA species within the same sample by size and sequence with base-pair resolution and discovered functionally specialized ecDNAs that amplify select enhancers or oncogene-coding sequences.

    View details for DOI 10.1038/s41588-022-01190-0

    View details for PubMedID 36253572

  • Deciphering the evolutionary dynamics of extrachromosomal DNA in human cancer NATURE GENETICS Lange, J. T., Mischel, P. S. 2022

    View details for DOI 10.1038/s41588-022-01183-z

    View details for Web of Science ID 000860213100001

    View details for PubMedID 36151323

  • Leveraging extrachromosomal DNA to fine-tune trials of targeted therapy for glioblastoma: opportunities and challenges. Nature reviews. Clinical oncology Noorani, I., Mischel, P. S., Swanton, C. 2022

    Abstract

    Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.

    View details for DOI 10.1038/s41571-022-00679-1

    View details for PubMedID 36131011

  • The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature genetics Lange, J. T., Rose, J. C., Chen, C. Y., Pichugin, Y., Xie, L., Tang, J., Hung, K. L., Yost, K. E., Shi, Q., Erb, M. L., Rajkumar, U., Wu, S., Taschner-Mandl, S., Bernkopf, M., Swanton, C., Liu, Z., Huang, W., Chang, H. Y., Bafna, V., Henssen, A. G., Werner, B., Mischel, P. S. 2022

    Abstract

    Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

    View details for DOI 10.1038/s41588-022-01177-x

    View details for PubMedID 36123406

  • Gene regulation on extrachromosomal DNA. Nature structural & molecular biology Hung, K. L., Mischel, P. S., Chang, H. Y. 2022

    Abstract

    Oncogene amplification on extrachromosomal DNA (ecDNA) is prevalent in human cancer and is associated with poor outcomes. Clonal, megabase-sized circular ecDNAs in cancer are distinct from nonclonal, small sub-kilobase-sized DNAs that may arise during normal tissue homeostasis. ecDNAs enable profound changes in gene regulation beyond copy-number gains. An emerging principle of ecDNA regulation is the formation of ecDNA hubs: micrometer-sized nuclear structures of numerous copies of ecDNAs tethered by proteins in spatial proximity. ecDNA hubs enable cooperative and intermolecular sharing of DNA regulatory elements for potent and combinatorial gene activation. The 3D context of ecDNA shapes its gene expression potential, selection for clonal heterogeneity among ecDNAs, distribution through cell division, and reintegration into chromosomes. Technologies for studying gene regulation and structure of ecDNA are starting to answer long-held questions on the distinct rules that govern cancer genes beyond chromosomes.

    View details for DOI 10.1038/s41594-022-00806-7

    View details for PubMedID 35948767

  • Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA. Nature Bergstrom, E. N., Luebeck, J., Petljak, M., Khandekar, A., Barnes, M., Zhang, T., Steele, C. D., Pillay, N., Landi, M. T., Bafna, V., Mischel, P. S., Harris, R. S., Alexandrov, L. B. 2022

    Abstract

    Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1-5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7-9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID)andAPOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

    View details for DOI 10.1038/s41586-022-04398-6

    View details for PubMedID 35140399

  • ecDNA hubs drive cooperative intermolecular oncogene expression. Nature Hung, K. L., Yost, K. E., Xie, L., Shi, Q., Helmsauer, K., Luebeck, J., Schopflin, R., Lange, J. T., Chamorro Gonzalez, R., Weiser, N. E., Chen, C., Valieva, M. E., Wong, I. T., Wu, S., Dehkordi, S. R., Duffy, C. V., Kraft, K., Tang, J., Belk, J. A., Rose, J. C., Corces, M. R., Granja, J. M., Li, R., Rajkumar, U., Friedlein, J., Bagchi, A., Satpathy, A. T., Tjian, R., Mundlos, S., Bafna, V., Henssen, A. G., Mischel, P. S., Liu, Z., Chang, H. Y. 2021

    Abstract

    Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

    View details for DOI 10.1038/s41586-021-04116-8

    View details for PubMedID 34819668

  • Extrachromosomal DNA: An Emerging Hallmark in Human Cancer. Annual review of pathology Wu, S., Bafna, V., Chang, H. Y., Mischel, P. S. 2021

    Abstract

    Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA, because of its nonchromosomal inheritance, drives high-copy-number oncogene amplification and enables tumors to evolve their genomes rapidly. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription, and the higher-order organization of ecDNA contributes to tumor pathogenesis. Consequently, patients whose cancers harbor ecDNA have significantly shorter survival. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. In this review, we discuss the current state of understanding of how ecDNAs form and function as well as how they contribute to drug resistance and accelerated cancer evolution. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    View details for DOI 10.1146/annurev-pathmechdis-051821-114223

    View details for PubMedID 34752712

  • Targeting glioblastoma signaling and metabolism with a re-purposed brain-penetrant drug. Cell reports Bi, J., Khan, A., Tang, J., Armando, A. M., Wu, S., Zhang, W., Gimple, R. C., Reed, A., Jing, H., Koga, T., Wong, I. T., Gu, Y., Miki, S., Yang, H., Prager, B., Curtis, E. J., Wainwright, D. A., Furnari, F. B., Rich, J. N., Cloughesy, T. F., Kornblum, H. I., Quehenberger, O., Rzhetsky, A., Cravatt, B. F., Mischel, P. S. 2021; 37 (5): 109957

    Abstract

    The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

    View details for DOI 10.1016/j.celrep.2021.109957

    View details for PubMedID 34731610

  • Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets. Nature reviews. Cancer Bi, J., Chowdhry, S., Wu, S., Zhang, W., Masui, K., Mischel, P. S. 2020; 20 (1): 57-70

    Abstract

    Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.

    View details for DOI 10.1038/s41568-019-0226-5

    View details for PubMedID 31806884

  • Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature Wu, S., Turner, K. M., Nguyen, N., Raviram, R., Erb, M., Santini, J., Luebeck, J., Rajkumar, U., Diao, Y., Li, B., Zhang, W., Jameson, N., Corces, M. R., Granja, J. M., Chen, X., Coruh, C., Abnousi, A., Houston, J., Ye, Z., Hu, R., Yu, M., Kim, H., Law, J. A., Verhaak, R. G., Hu, M., Furnari, F. B., Chang, H. Y., Ren, B., Bafna, V., Mischel, P. S. 2019

    Abstract

    Oncogenes are commonly amplified on particles of extrachromosomal DNA (ecDNA) in cancer1,2, but our understanding of the structure of ecDNA and its effect on gene regulation is limited. Here, by integrating ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing, we demonstrate the structure of circular ecDNA. Pan-cancer analyses reveal that oncogenes encoded on ecDNA are among the most highly expressed genes in the transcriptome of the tumours, linking increased copy number with high transcription levels. Quantitative assessment of the chromatin state reveals that although ecDNA is packaged into chromatin with intact domain structure, it lacks higher-order compaction that is typical of chromosomes and displays significantly enhanced chromatin accessibility. Furthermore, ecDNA is shown to have a significantly greater number of ultra-long-range interactions with active chromatin, which provides insight into how the structure of circular ecDNA affects oncogene function, and connects ecDNA biology with modern cancer genomics and epigenetics.

    View details for DOI 10.1038/s41586-019-1763-5

    View details for PubMedID 31748743

  • Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling. Cell metabolism Bi, J., Ichu, T., Zanca, C., Yang, H., Zhang, W., Gu, Y., Chowdhry, S., Reed, A., Ikegami, S., Turner, K. M., Zhang, W., Villa, G. R., Wu, S., Quehenberger, O., Yong, W. H., Kornblum, H. I., Rich, J. N., Cloughesy, T. F., Cavenee, W. K., Furnari, F. B., Cravatt, B. F., Mischel, P. S. 2019

    Abstract

    Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

    View details for DOI 10.1016/j.cmet.2019.06.014

    View details for PubMedID 31303424

  • Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nature reviews. Cancer Verhaak, R. G., Bafna, V., Mischel, P. S. 2019; 19 (5): 283-288

    Abstract

    Recent reports have demonstrated that oncogene amplification on extrachromosomal DNA (ecDNA) is a frequent event in cancer, providing new momentum to explore a phenomenon first discovered several decades ago. The direct consequence of ecDNA gains in these cases is an increase in DNA copy number of the oncogenes residing on the extrachromosomal element. A secondary effect, perhaps even more important, is that the unequal segregation of ecDNA from a parental tumour cell to offspring cells rapidly increases tumour heterogeneity, thus providing the tumour with an additional array of responses to microenvironment-induced and therapy-induced stress factors and perhaps providing an evolutionary advantage. This Perspectives article discusses the current knowledge and potential implications of oncogene amplification on ecDNA in cancer.

    View details for DOI 10.1038/s41568-019-0128-6

    View details for PubMedID 30872802

    View details for PubMedCentralID PMC7168519

  • NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature Chowdhry, S., Zanca, C., Rajkumar, U., Koga, T., Diao, Y., Raviram, R., Liu, F., Turner, K., Yang, H., Brunk, E., Bi, J., Furnari, F., Bafna, V., Ren, B., Mischel, P. S. 2019; 569 (7757): 570-575

    Abstract

    Precision oncology hinges on linking tumour genotype with molecularly targeted drugs1; however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge2. Here we show that tissue context is the major determinant of dependence on the nicotinamide adenine dinucleotide (NAD) metabolic pathway in cancer. By analysing more than 7,000 tumours and 2,600 matched normal samples of 19 tissue types, coupled with mathematical modelling and extensive in vitro and in vivo analyses, we identify a simple and actionable set of 'rules'. If the rate-limiting enzyme of de novo NAD synthesis, NAPRT, is highly expressed in a normal tissue type, cancers that arise from that tissue will have a high frequency of NAPRT amplification and be completely and irreversibly dependent on NAPRT for survival. By contrast, tumours that arise from normal tissues that do not express NAPRT highly are entirely dependent on the NAD salvage pathway for survival. We identify the previously unknown enhancer that underlies this dependence. Amplification of NAPRT is shown to generate a pharmacologically actionable tumour cell dependence for survival. Dependence on another rate-limiting enzyme of the NAD synthesis pathway, NAMPT, as a result of enhancer remodelling is subject to resistance by NMRK1-dependent synthesis of NAD. These results identify a central role for tissue context in determining the choice of NAD biosynthetic pathway, explain the failure of NAMPT inhibitors, and pave the way for more effective treatments.

    View details for DOI 10.1038/s41586-019-1150-2

    View details for PubMedID 31019297

    View details for PubMedCentralID PMC7138021

  • Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity NATURE Turner, K. M., Deshpande, V., Beyter, D., Koga, T., Rusert, J., Lee, C., Li, B., Arden, K., Ren, B., Nathanson, D. A., Kornblum, H. I., Taylor, M. D., Kaushal, S., Cavenee, W. K., Wechsler-Reya, R., Furnari, F. B., Vandenberg, S. R., Rao, P., Wahl, G. M., Bafna, V., Mischel, P. S. 2017; 543 (7643): 122-+

    Abstract

    Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.

    View details for DOI 10.1038/nature21356

    View details for Web of Science ID 000395671500045

    View details for PubMedID 28178237

    View details for PubMedCentralID PMC5334176

  • Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science (New York, N.Y.) Nathanson, D. A., Gini, B., Mottahedeh, J., Visnyei, K., Koga, T., Gomez, G., Eskin, A., Hwang, K., Wang, J., Masui, K., Paucar, A., Yang, H., Ohashi, M., Zhu, S., Wykosky, J., Reed, R., Nelson, S. F., Cloughesy, T. F., James, C. D., Rao, P. N., Kornblum, H. I., Heath, J. R., Cavenee, W. K., Furnari, F. B., Mischel, P. S. 2014; 343 (6166): 72-6

    Abstract

    Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.

    View details for DOI 10.1126/science.1241328

    View details for PubMedID 24310612

    View details for PubMedCentralID PMC4049335