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 language | American English |
|---|---|
| Pages (from-to) | 928-949 |
| Number of pages | 22 |
| Journal | Cancer Discovery |
| Volume | 13 |
| Issue number | 4 |
| DOIs | |
| State | Published - 1 Apr 2023 |
Bibliographical note
Funding Information:We gratefully acknowledge the contributions of our patients who participated in the study and their families. This work utilized the computational resources of the NIH HPC Biowulf cluster (http:// hpc.nih.gov). This work was supported by the intramural programs of the Center for Cancer Research, National Cancer Institute (ZIA BC 011793). We are grateful to Michael Kruhlak, Langston Lim, and Andy Tran [Confocal Microscopy Core Facility, Center for Cancer Research (CCR), NCI, NIH], Liz Conner, Madeline Wong, and Steven Shema (CCR Genomics Core), and Jyoti Shetty (CCR core sequencing facility).
Funding Information:
L. Rinaldi reports other support from Delfi Diagnostics and an EMBO long-term fellowship outside the submitted work. J. Gutin is a cofounder of Senseera. N. Roper reports grants from Taiho Pharmaceuticals and ADC Therapeutics outside the submitted work. N. Friedman reports grants from the European Research Council and the Israel Science Foundation during the conduct of the study; personal fees from Senseera outside the submitted work; a patent for diagnostic use of cell-free DNA chromatin immunoprecipitation pending to The Hebrew University of Jerusalem; and is cofounder of Senseera. A. Thomas reports grants from EMD Serono Research and Development Institute, AstraZeneca, Tarveda Therapeutics,
Funding Information:
We gratefully acknowledge the contributions of our patients who participated in the study and their families. This work utilized the computational resources of the NIH HPC Biowulf cluster (http:// hpc.nih.gov). This work was supported by the intramural programs of the Center for Cancer Research, National Cancer Institute (ZIA BC 011793). We are grateful to Michael Kruhlak, Langston Lim, and Andy Tran [Confocal Microscopy Core Facility, Center for Cancer Research (CCR), NCI, NIH], Liz Conner, Madeline Wong, and Steven Shema (CCR Genomics Core), and Jyoti Shetty (CCR core sequencing facility). The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Publisher Copyright:
© 2023 American Association for Cancer Research.
