Disentangling oncogenic amplicons in esophageal adenocarcinoma
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Alvin Wei Tian Ng Dylan Peter McClurg Ben Wesley Shahriar A Zamani Emily Black Ahmad Miremadi Olivier Giger Rogier ten Hoopen Ginny Devonshire Aisling M Redmond Nicola Grehan Sriganesh Jammula Adrienn Blasko Xiaodun Li Samuel Aparicio Simon Tavaré Paul AW Edwards Nicola Grehan Barbara Nutzinger Christine Loreno Sujath Abbas Adam Freeman Elizabeth C Smyth Maria O’Donovan Ahmad Miremadi Shalini Malhotra Monika Tripathi Calvin Cheah Hannah Coles Curtis Millington Matthew Eldridge Maria Secrier Sriganesh Jammula Jim Davies Charles Crichton Nick Carroll Richard H Hardwick Peter Safranek Andrew Hindmarsh Vijayendran Sujendran Stephen J Hayes Yeng Ang Andrew Sharrocks Shaun R Preston Izhar Bagwan Vicki Save Richard JE Skipworth Ted R Hupp J Robert O’Neill Olga Tucker Andrew Beggs Philippe Taniere Sonia Puig Gianmarco Contino Timothy J Underwood Robert C Walker Ben L Grace Jesper Lagergren James Gossage Andrew Davies Fuju Chang Ula Mahadeva Vicky Goh Francesca Ciccarelli Grant Sanders Richard Berrisford David Chan Ed Cheong Bhaskar Kumar L Sreedharan Simon L Parsons Irshad Soomro Philip Kaye John Saunders Laurence Lovat Rehan Haidry Michael Scott Sharmila Sothi Suzy Lishman George B Hanna Christopher J Peters Krishna Moorthy Anna Grabowska Richard Turkington Damian McManus Helen Coleman Russell D Petty Freddie Bartlet Karol Nowicki-Osuch Rebecca C Fitzgerald
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Abstract
Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.
Journal details
Journal
Nature Communications
Volume
15
Issue number
1
Pages
4074
Available online
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10.1038/s41467-024-47619-4
Europe PubMed Central
38744814
Pubmed
38744814
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