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Esophageal Cancer, Precancer Study Points to Extrachromosomal DNA Appearance

NEW YORK – New research suggests extrachromosomal DNA (ecDNA) containing amplified oncogenes may be present not only in some esophageal cancers but also in individuals with Barrett's esophagus, a condition that can progress to esophageal cancer in a small subset of affected individuals.

"These findings have profound implications for our understanding of ecDNA in tumor pathogenesis — it can occur during cancerous transformation and that ecDNAs can be selected for during cancer progression," co-corresponding author Paul Mischel, a pathologist at Stanford University School of Medicine, said in an email, noting that the work "highlights the power and diversity of ecDNA as a fundamental process in cancer."

As they reported in Nature on Wednesday, the researchers did whole-genome sequencing on 206 biopsy samples from individuals who already had developed esophageal adenocarcinoma, along with participants being followed for Barrett's esophagus. Along with those patient cohorts, which were enrolled at the University of Cambridge, they also analyzed data for six early- and 14 late-stage esophageal carcinoma cases profiled by the Cancer Genome Atlas project.

The team also used whole-genome sequencing and histological analyses to profile multiple sample regions apiece at two or more time points for 40 Barrett's esophagus patients who went on to develop esophageal cancer and 40 who did not — individuals who were enrolled prospectively at the Fred Hutchinson Cancer Center.

"Some researchers have looked at the phylogenetic trees of some cancers with ecDNAs and decided … it must be a late event, after the cancer has formed, and therefore, not something that you can act on necessarily," Mischel explained. "We thought that this interpretation was wrong."

In participants profiled in the UK, the investigators identified ecDNA in nearly one-quarter of the early-stage esophageal cancers that developed in individuals with Barrett's esophagus and in 43 percent of the late-stage esophageal cancer cases. Likewise, around one-third of the patients from Fred Hutch who developed esophageal cancer had ecDNA present in one or more pre-cancer samples.

When the team took a closer look at the Barrett's esophagus cases that progressed to esophageal cancer, meanwhile, it saw elevated ecDNA levels in pre-cancerous samples and in samples from tissues showing high-grade dysplasia.

Such ecDNAs harbored cancer-promoting oncogenes such as KRAS, MYC, and ERBB2, and genes with immunomodulatory functions, the investigators reported, and tended to co-occur with TP53 gene alterations. Together, these and other patterns found in the Barrett's esophagus and esophageal cancer cases suggested that the ecDNA structures likely help drive cancer formation rather than developing after it is already present.

"These results provide new mechanistic insight into ecDNA as an important molecular event that can occur in the transformation of pre-cancer to cancer, suggesting that earlier detection and intervention may make a difference for patients," Mischel said.

He noted that additional research will be needed to delve into the mechanisms of ecDNA development and ways to combat them, and to develop methods for detecting ecDNA in samples that do not undergo whole-genome sequencing.

"Although present in many types of human cancer, extrachromosomal DNA was thought to be non-existent in normal tissues," University of Texas Southwestern Medical Center hematology and oncology researcher David Wang wrote in an accompanying commentary in Nature, noting that the data on Barrett's esophagus cancer predisposition tissue "provide evidence that this DNA might help to drive non-cancerous tissue to become cancerous."

Even so, he cautioned that it remains to be seen whether ecDNA provides predictive biomarker insights for individuals who have advanced to high-grade dysplasia.

"The standard clinical care for high-grade dysplasia is to use an endoscopic technique to eradicate Barrett's esophagus tissue, and intervening at this point removes the need to predict who might progress," Wang wrote, arguing that "future work should focus on therapeutic interventions relating to extrachromosomal DNA."