Disentangling oncogenic amplicons in esophageal adenocarcinoma
Creators: name: Ng, Alvin Wei Tian
name: McClurg, Dylan Peter
name: Wesley, Ben
name: Zamani, Shahriar A
name: Black, Emily
name: Miremadi, Ahmad
name: Giger, Olivier
name: Hoopen, Rogier ten
name: Devonshire, Ginny
name: Redmond, Aisling M
name: Grehan, Nicola
name: Jammula, Sriganesh
name: Blasko, Adrienn
name: Li, Xiaodun
name: Aparicio, Samuel
name: Tavaré, Simon
name: Edwards, Paul AW
name: Nutzinger, Barbara
name: Loreno, Christine
name: Abbas, Sujath
name: Freeman, Adam
name: Smyth, Elizabeth C
name: O’Donovan, Maria
name: Malhotra, Shalini
name: Tripathi, Monika
name: Cheah, Calvin
name: Coles, Hannah
name: Millington, Curtis
name: Eldridge, Matthew
name: Secrier, Maria
name: Davies, Jim
name: Crichton, Charles
name: Carroll, Nick
name: Hardwick, Richard H
name: Safranek, Peter
name: Hindmarsh, Andrew
name: Sujendran, Vijayendran
name: Hayes, Stephen J
name: Ang, Yeng
name: Sharrocks, Andrew
name: Preston, Shaun R
name: Bagwan, Izhar
name: Save, Vicki
name: Skipworth, Richard JE
name: Hupp, Ted R
name: O’Neill, J Robert
name: Tucker, Olga
name: Beggs, Andrew
name: Taniere, Philippe
name: Puig, Sonia
name: Contino, Gianmarco
name: Underwood, Timothy J
name: Walker, Robert C
name: Grace, Ben L
name: Lagergren, Jesper
name: Gossage, James
name: Davies, Andrew
name: Chang, Fuju
name: Mahadeva, Ula
name: Goh, Vicky
name: Ciccarelli, Francesca D
name: Sanders, Grant
name: Berrisford, Richard
name: Chan, David
name: Cheong, Ed
name: Kumar, Bhaskar
name: Sreedharan, L
name: Parsons, Simon L
name: Soomro, Irshad
name: Kaye, Philip
name: Saunders, John
name: Lovat, Laurence
name: Haidry, Rehan
name: Scott, Michael
name: Sothi, Sharmila
name: Lishman, Suzy
name: Hanna, George B
name: Peters, Christopher J
name: Moorthy, Krishna
name: Grabowska, Anna
name: Turkington, Richard
name: McManus, Damian
name: Coleman, Helen
name: Petty, Russell D
name: Bartlet, Freddie
name: Nowicki-Osuch, Karol
name: Fitzgerald, Rebecca C
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology

description: 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.