Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes

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 CaravacaSevilay Turan, Tsai Wei Shen, 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Onco-genic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroen-docrine 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 nonin-vasively 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.

Original languageAmerican English
Pages (from-to)928-949
Number of pages22
JournalCancer Discovery
Volume13
Issue number4
DOIs
StatePublished - 3 Apr 2023

Bibliographical note

Publisher Copyright:
© 2023 American Association for Cancer Research.

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