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Disentangling oncogenic amplicons in esophageal adenocarcinoma

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posted on 2024-05-20, 13:11 authored by 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, Barbara Nutzinger, Christine Loreno, Sujath Abbas, Adam Freeman, Elizabeth C Smyth, Maria O’Donovan, Shalini Malhotra, Monika Tripathi, Calvin Cheah, Hannah Coles, Curtis Millington, Matthew Eldridge, Maria Secrier, 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 D 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
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.

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