Lorenzo de la Rica, Research Programme Manager at Cancer Grand Challenges, provides his insights on the importance of the latest paper from the Cancer Grand Challenges eDyNAmiC team, tackling the extrachromosomal DNA challenge.
The latest paper from the eDyNAmiC team, published today in Nature, beautifully dissects the role of extrachromosomal DNA (ecDNA) in patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus (BE), a precancerous condition that can develop into EAC.
By using two of the most detailed BE cohorts available worldwide (Cambridge UK cross-sectional cohort, led by Rebecca C. Fitzgerald, and the Fred Hutchinson Cancer Center prospectively collected cohort, led by Thomas G. Paulson), the team found that the frequency of ecDNAs increased during cancer progression, with more advanced disease stages showing increased ecDNA copy number and structural complexity.
ecDNA presence was found to be enriched among patients with BE who later developed EAC compared to patients who did not go on to develop EAC. Surprisingly, the ecDNAs in samples collected from patients who did progress to EAC harboured diverse oncogenes and immunomodulatory genes.
The team’s findings demonstrate that ecDNA in BE can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.
I think this this paper is important because:
It’s one of the first studies to demonstrate that ecDNAs appear early, before the development of full-blown cancer, and that their presence is strongly associated with progression to cancer. The team has demonstrated that ecDNAs confer a strong selective advantage to the BE clones that eventually progress to EAC (tumour evolution from precancer to cancer). This is a proof-of-concept for what the team may be able to unveil in many other aggressive tumour types.
ecDNAs are present in some of the most aggressive forms of cancer. As ecDNA formation may represent a particularly potent driver of transformation to cancer, it may represent an opportunity for specific therapeutic intervention, which the team is currently exploring - one example being Ben Cravatt’s (Scripps Research Institute, US) innovative covalent chemistry probes for targeting ecDNA pathways.
The study was led by Paul Mischel (eDyNAmiC team lead, Stanford Medicine, US), Howard Chang (eDyNAmiC co-investigator, Stanford University, US), Thomas Paulson (Fred Hutchison Cancer Center, US), Sihan Wu (Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center) Vineet Bafna (eDyNAmiC co-investigator, University of California, San Diego) and Rebecca Fitzgerald (University of Cambridge).
Read the paper in Nature and the “Tweetorial” from the first author, Cancer Grand Challenges Future Leader Jens Luebeck here. A Nature News and Views commentary accompanies the paper.
Find out more about the work of the eDyNAmiC team.
The eDyNAmiC team is funded by Cancer Research UK and the National Cancer Institute.
AACR Annual Meeting 2023
Come and visit Cancer Grand Challenges at stand 707 at the AACR Annual Meeting 2023. Learn about our new challenges and $25m funding opportunity, as well as the exciting research coming out of our funded teams.
Team eDyNAmiC’s Jens Luebeck, postdoctoral researcher at the University of California, San Diego and first author of the paper, will be presenting a poster at the 2023 AACR Annual Meeting about this project. To find out more about the research, visit Jens’ poster on 17 April 2023, 1:30 PM - 5:00 PM:
Session: PO.BCS01.01 - Bioinformatics Applications in Cancer Biology 2
Poster: 3130 - Extrachromosomal DNA in the cancerous transformation of Barrett’s esophagus
Location: Poster #16 in section 32