American Association for Cancer Research

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Figure 1 extended data from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes

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posted on 2023-04-04, 15:40 authored by Lőrinc Sándor Pongor, Christopher W. Schultz, Lorenzo Rinaldi, Darawalee Wangsa, Christophe E. Redon, Nobuyuki Takahashi, Gavriel Fialkoff, Parth Desai, Yang Zhang, Sandra Burkett, Nadav Hermoni, Noa Vilk, Jenia Gutin, Rona Gergely, Yongmei Zhao, Samantha Nichols, Rasa Vilimas, Linda Sciuto, Chante Graham, Juan Manuel Caravaca, Sevilay Turan, Shen Tsai-wei, Vinodh N. Rajapakse, Rajesh Kumar, Deep Upadhyay, Suresh Kumar, Yoo Sun Kim, Nitin Roper, Bao Tran, Stephen M. Hewitt, David E. Kleiner, Mirit I. Aladjem, Nir Friedman, Gordon L. Hager, Yves Pommier, Thomas Ried, Anish Thomas

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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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. 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

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