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

Abstract

Small-cell lung cancer 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 non-neuroendocrine cell states is 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 MYC amplifications and driver fusions in SCLC. 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 non-invasively 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 describe a new mechanism that governs MYC-driven SCLC heterogeneity. ecDNA-enabled transcriptional flexibility may explain the significantly worse survival outcomes of SCLC tumors harboring complex ecDNA amplifications.

CytoCellDB: A Resource Database For Classification and Analysis of Extrachromosomal DNA in Cancer

“…Several recent efforts 1,2,15 characterize ecDNA in 112 cancer cell lines, where nearly half of the cell lines are lung cancer model systems ( Fig. 1E ).…”

FORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS

“…Transcriptional profiling has also allowed us to conclude that the hESC-derived tumors arising from RPM RUES2 cells belong to the SCLC-N subtype, one of the major subtypes of SCLC now recognized by several laboratories and clinicians studying SCLC. It is unclear whether SCLC-N truly represents a subtype of SCLC with distinct outcomes and therapeutic sensitivities (45), or rather a snapshop from a continuum in tumor evolution driven [principally] by MYC towards an aggressive, recalcitrant disease (46, 47). Future studies of stem cell-derived SCLC should consider ways to generate tumors that model the other common subtypes including SCLC-P and SCLC-I (“inflamed” SCLC) (45).…”

Extrachromosomal circular DNA in colorectal cancer: biogenesis, function and potential as therapeutic target

“…2D). This feature of extrachromosomal oncogene amplification has been reported to lead to up to several hundreds of ecDNAs in a single CRC, as well as other types of cancer cells [1,[79][80][81]. This has been associated with rapid respond and adaptation to selective pressures, as well as increased of therapeutic resistance [6,82] (Fig.…”

“…The ecDNAs hub significantly expands the concept of CRC genetic heterogeneity, as cancer cells can carry ecDNAs with different oncogenes and diverse regulatory sequences, which may interact with each other or integrate into larger circular molecules. The randomness of offspring distribution, the fusion of ecDNA to form larger pieces, and the integration of ecDNA into chromosomes will affect the spatial clustering [81]. The ecDNA hub intrigues the concept that gaining survival advantages from clonal competition among cancer cells could take place through clonal cooperation among ecDNA molecules [3].…”