학술논문
Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes.
Document Type
Academic Journal
Author
Pongor LS; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; HCEMM Cancer Genomics and Epigenetics Research Group, Szeged, Hungary.; Schultz CW; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Rinaldi L; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Wangsa D; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.; Redon CE; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Takahashi N; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Fialkoff G; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.; Desai P; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Zhang Y; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Burkett S; Molecular Cytogenetic Core Facility, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland.; Hermoni N; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.; School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.; Vilk N; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.; School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.; Gutin J; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.; Gergely R; Department of Biochemistry and Molecular Pharmacology, NYU, New York, New York.; Laura and Isaac Perlmutter NYU Cancer Center, New York, New York.; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, New York.; Zhao Y; Bioinformatics and Computational Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.; Nichols S; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Vilimas R; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Sciuto L; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Graham C; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Caravaca JM; Bioinformatics and Computational Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.; Turan S; Bioinformatics and Computational Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland.; Tsai-Wei S; Howard Hughes Medical Institute, New York University Grossman School of Medicine, New York, New York.; Rajapakse VN; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Kumar R; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Upadhyay D; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Kumar S; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Kim YS; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Roper N; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Tran B; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland.; Hewitt SM; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Kleiner DE; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Aladjem MI; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Friedman N; School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.; School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.; Hager GL; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Pommier Y; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.; Ried T; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.; Thomas A; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Source
Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
Subject
Language
English
Abstract
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.
Significance: 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. This article is highlighted in the In This Issue feature, p. 799.
(©2023 American Association for Cancer Research.)
Significance: 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. This article is highlighted in the In This Issue feature, p. 799.
(©2023 American Association for Cancer Research.)