NEW YORK – A collection of new studies has spelled out the prevalence and potential roles that extrachromosomal DNA (ecDNA) can play in cancer development, treatment response, and outcomes, providing insights that may inform future efforts to personalize tumor profiling and treatment strategies.
The work builds on research published over the past decade, linking oncogene amplification, enhanced oncogene transcription, and higher-than-usual gene expression to ecDNA, which was previously considered rare and of limited biological relevance.
Those earlier efforts to characterize ecDNA features and their contributions to specific cancer types provided a glimpse at the ways ecDNAs could influence cancer development and tumor evolution, prompting more detailed analyses on such processes with help from Cancer Research UK's Cancer Grand Challenges program.
Stanford University researcher Paul Mischel, a co-corresponding author on all three new studies, explained in an email that the Cancer Grand Challenges team eDyNAmiC, which he led, and the TRACERx consortium led by Francis Crick Institute and University College London researcher Charles Swanton and UCL researcher Mariam Jamal-Hanjani "reveals the origins, patterns, and clinical impact of ecDNA … in human cancer, and demonstrates its association with poor outcomes for patients."
For the first of the studies, published in Nature on Wednesday, a TRACERx team led by Mischel, Swanton, and Jamal-Hanjani considered genome sequence data spanning more than 15,800 tumor samples across more than three dozen cancer types in 14,778 cancer patient participants from the 100,000 Genomes Project.
"By analyzing the largest available single collection of whole-genome-sequenced samples from patients with cancer currently available, we demonstrate the remarkable diversity of ecDNA elements across cancer," authors of that study reported, "illuminating the associated tissue and genetic context and the mutation processes to which ecDNA is linked."
The team tracked down ecDNA in just over 17 percent of the tumors tested, though the precise ecDNA patterns found varied depending on the tissue of origin involved. On the functional side, these ecDNAs appeared to amplify genes involved in tumor aggressiveness and immune suppression, while muddling regulatory activity in the genome.
Together, the study authors explained, the findings "shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumor growth signals, alter transcriptional landscapes, and suppress the immune system."
In another Nature study from the Cancer Grand Challenges team eDyNAmiC, Mischel and colleagues at Stanford and other international centers turned to single-cell sequencing Circle-seq, imaging, chemical testing, and computational modeling — in combination with whole-genome sequence data from the Cancer Genome Atlas project — to analyze ecDNA inheritance patterns and their consequences in cancer.
That work pointed to "underlying intermolecular interactions between distinct ecDNAs that enable co-selection and co-amplification of multiple oncogenes," Mischel noted, "supporting cooperation amongst heterogeneous ecDNAs and contributing to continued diversification of cancer genomes."
For example, findings from the study suggested that cancer cells may contain multiple co-occurring ecDNAs that segregate with one another during mitotic cell division, affecting the evolutionary trajectory and biological capabilities of the tumor.
Finally, a Stanford University-led group working on the eDyNAmiC team outlined a strategy for targeting ecDNAs in cancer by boosting synthetic lethal interactions between transcription and replication stress in ecDNA-containing tumors.
In particular, the investigators found that they could curb the growth of tumors containing ecDNA by genetically or pharmacologically targeting an S-phase checkpoint kinase enzyme encoded by CHK1 that gets activated in response to DNA double-strand breaks stemming from ecDNA-related transcription-replication conflicts.
Based on these and other findings, a San Diego-based oncology company called Boundless Bio — cofounded by Mischel and co-senior author and Stanford researcher Howard Chang — is reportedly sponsoring a Phase I/II study focused on oncogene-amplified locally advanced or metastatic tumors treated with a CHK1 inhibitor.
"Our work demonstrates the feasibility of a synthetic lethality of cancer-specific cellular excess to turn the molecular advantages of ecDNA in cancer against itself," the authors wrote, noting that "results presented here suggest a promising strategy for a next-generation CHK1 inhibitor to target ecDNA-containing cancers."