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Pan-Cancer Study Reveals Extrachromosomal DNA Frequency, Possible Survival Impacts

NEW YORK – The presence of circular, centromere-free extrachromosomal DNA (ecDNA) amplifications in a patient's tumor may portend poor cancer outcomes, according to newly published research conducted by a team from Jackson Laboratory for Genomic Medicine and the University of California at San Diego.

"Our results present the landscape of ecDNA across cancer," Hoon Kim, at the Jackson Lab, and Nam-Phuong Nguyen, at UCSD, the study's co-first authors, and their colleagues reported. "Given cancer's heterogeneity, it is certain that diversity in ecDNA structure and behavior exists between different cancer types." 

As they reported in Nature Genetics on Monday, the researchers relied on computational approaches to find, and track the frequency, of ecDNA amplification events in as many as 3,212 tumors tested with genome sequencing, RNA sequencing, or ATAC-seq. Such amplifications were missing from normal tissue samples, but they did turn up across cancer types — all but the blood cancers considered, that is — often carrying oncogenes along with them.

"Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA," the authors reported, noting that ecDNA amplification events "resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions."

Notably, the team saw signs that the presence of ecDNA in a tumor generally corresponded with poorer patient outcomes compared with non-ecDNA tumors from the same cancer types, pointing to a potential role for ecDNA in tumor aggressiveness or the possibility of using the rogue DNA prognostically.

"The potential to leverage the presence of ecDNAs in human cancers for diagnostic or therapeutic purposes provides a link between cancer genomics and broad utility for patient populations," the authors explained.

While DNA amplifications occurring in the ecDNA context have been difficult to tally with limited cytogenetic analyses in the past, the team noted, the advent of circular DNA library enrichment methods and refined whole-genome-based analytical methods have made it possible to get a more comprehensive look at ecDNAs and their consequences in cancer.

For their own analyses, the researchers initially validated a tool called AmpliconArchitect — designed to reconstruct focal amplification structures in the tumors based on whole-genome sequence data — before applying it to available genome sequence data for more than 3,200 tumor samples and 1,810 non-neoplastic samples, uncovering 460 tumors with at least one circular amplicon.

When the team dug into two dozen recurrent oncogene amplifications, it found that more than one-third recurrently turned up on circular amplicons. That was also the case for more than half of the oncogenes marked by particularly pronounced amplification events.

Bringing in additional RNA-seq and ATAC-seq data provided the researchers with a chance to look at the impact of some ecDNAs and the oncogenes they carry in cancer, while five-year survival data for patients with or without circular amplicons in their tumors revealed the potential differences in outcomes coinciding with the ecDNAs.

While additional details are yet to be discerned, the authors suggested that future studies of structural variation and other features in cancer "will aid improved understanding of the mechanisms that create genomic rearrangements including ecDNA."

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