{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:50:17Z","timestamp":1792803017687,"version":"4.5.0"},"reference-count":81,"publisher":"American Association for Cancer Research (AACR)","issue":"4","funder":[{"name":"National Cancer Institute","award":["ZIA BC 011793"],"award-info":[{"award-number":["ZIA BC 011793"]}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions. ecDNAs bring to proximity enhancer elements and oncogenes, creating SCLC transcription-amplifying units, driving exceptionally high MYC gene dosage. We demonstrate that cell-free nucleosome profiling can noninvasively detect ecDNA amplifications in plasma, facilitating its genome-wide interrogation in SCLC and other cancers. Altogether, our work provides the first comprehensive map of SCLC ecDNA and describes a new mechanism that governs MYC-driven SCLC heterogeneity. ecDNA-enabled transcriptional flexibility may explain the significantly worse survival outcomes of SCLC harboring complex ecDNA amplifications.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>MYC drives SCLC progression, but the genetic basis of MYC-driven SCLC evolution is unknown. Using SCLC as a paradigm, we report how ecDNA amplifications function as MYC-amplifying units, fostering tumor plasticity and a high degree of tumor heterogeneity.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 799<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0796","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T09:09:14Z","timestamp":1675069754000},"page":"928-949","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":135,"title":["Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-4628","authenticated-orcid":false,"given":"L\u0151rinc S\u00e1ndor","family":"Pongor","sequence":"first","affiliation":[{"name":"1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."},{"name":"2HCEMM Cancer Genomics and Epigenetics Research Group, Szeged, Hungary."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-2847","authenticated-orcid":false,"given":"Christopher W.","family":"Schultz","sequence":"additional","affiliation":[{"name":"1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-4205","authenticated-orcid":false,"given":"Lorenzo","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"3Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8585-3077","authenticated-orcid":false,"given":"Darawalee","family":"Wangsa","sequence":"additional","affiliation":[{"name":"4Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2799-2778","authenticated-orcid":false,"given":"Christophe E.","family":"Redon","sequence":"additional","affiliation":[{"name":"1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8592-6528","authenticated-orcid":false,"given":"Nobuyuki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer 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for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5476-4028","authenticated-orcid":false,"given":"Sandra","family":"Burkett","sequence":"additional","affiliation":[{"name":"6Molecular Cytogenetic Core Facility, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2396-0832","authenticated-orcid":false,"given":"Nadav","family":"Hermoni","sequence":"additional","affiliation":[{"name":"5School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel."},{"name":"7School of Medicine, The Hebrew University of Jerusalem, Jerusalem, 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