Disentangling oncogenic amplicons in esophageal adenocarcinoma

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; OCCAMS Consortium; Karol Nowicki-Osuch; Rebecca C. Fitzgerald; Russell D. Petty

doi:10.1038/s41467-024-47619-4

Disentangling oncogenic amplicons in esophageal adenocarcinoma

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
, OCCAMS Consortium
, Karol Nowicki-Osuch
, Rebecca C. Fitzgerald (Lead / Corresponding author)
, Russell D. Petty (Research group member)

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

96 Downloads (Pure)

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.

Original language	English
Article number	4074
Number of pages	13
Journal	Nature Communications
Volume	15
Early online date	14 May 2024
DOIs	https://doi.org/10.1038/s41467-024-47619-4
Publication status	E-pub ahead of print - 14 May 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-47619-4Licence: CC BY

Final published versionFinal published version, 9.91 MBLicence: CC BY

Cite this

Ng, A. W. T., McClurg, D. P., Wesley, B., Zamani, S. A., Black, E., Miremadi, A., Giger, O., Hoopen, R. T., Devonshire, G., Redmond, A. M., Grehan, N., Jammula, S., Blasko, A., Li, X., Aparicio, S., Tavaré, S., OCCAMS Consortium, Nowicki-Osuch, K., Fitzgerald, R. C., & Petty, R. D. (2024). Disentangling oncogenic amplicons in esophageal adenocarcinoma. Nature Communications, 15, Article 4074. Advance online publication. https://doi.org/10.1038/s41467-024-47619-4

@article{ce45e83e6eb94d4fb789dc202301ac36,

title = "Disentangling oncogenic amplicons in esophageal adenocarcinoma",

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{\textquoteright} 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.",

author = "Ng, \{Alvin Wei Tian\} and McClurg, \{Dylan Peter\} and Ben Wesley and Zamani, \{Shahriar A.\} and Emily Black and Ahmad Miremadi and Olivier Giger and Hoopen, \{Rogier ten\} and Ginny Devonshire and Redmond, \{Aisling M.\} and Nicola Grehan and Sriganesh Jammula and Adrienn Blasko and Xiaodun Li and Samuel Aparicio and Simon Tavar{\'e} and \{OCCAMS Consortium\} and Karol Nowicki-Osuch and Fitzgerald, \{Rebecca C.\} and Edwards, \{Paul A. W.\} and Nicola Grehan and Barbara Nutzinger and Christine Loreno and Sujath Abbas and Adam Freeman and Smyth, \{Elizabeth C.\} and Maria O{\textquoteright}Donovan and Ahmad Miremadi and Shalini Malhotra and Monika Tripathi and Calvin Cheah and Hannah Coles and Curtis Millington and Matthew Eldridge and Maria Secrier and Sriganesh Jammula and Jim Davies and Charles Crichton and Nick Carroll and Hardwick, \{Richard H.\} and Peter Safranek and Andrew Hindmarsh and Vijayendran Sujendran and Hayes, \{Stephen J.\} and Yeng Ang and Andrew Sharrocks and Preston, \{Shaun R.\} and Izhar Bagwan and Vicki Save and Skipworth, \{Richard J.E.\} and Walker, \{Robert C.\} and Hanna, \{George B.\} and Petty, \{Russell D.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = may,

day = "14",

doi = "10.1038/s41467-024-47619-4",

language = "English",

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Ng, AWT, McClurg, DP, Wesley, B, Zamani, SA, Black, E, Miremadi, A, Giger, O, Hoopen, RT, Devonshire, G, Redmond, AM, Grehan, N, Jammula, S, Blasko, A, Li, X, Aparicio, S, Tavaré, S, OCCAMS Consortium, Nowicki-Osuch, K, Fitzgerald, RC & Petty, RD 2024, 'Disentangling oncogenic amplicons in esophageal adenocarcinoma', Nature Communications, vol. 15, 4074. https://doi.org/10.1038/s41467-024-47619-4

TY - JOUR

T1 - Disentangling oncogenic amplicons in esophageal adenocarcinoma

AU - Ng, Alvin Wei Tian

AU - McClurg, Dylan Peter

AU - Wesley, Ben

AU - Zamani, Shahriar A.

AU - Black, Emily

AU - Miremadi, Ahmad

AU - Giger, Olivier

AU - Hoopen, Rogier ten

AU - Devonshire, Ginny

AU - Redmond, Aisling M.

AU - Grehan, Nicola

AU - Jammula, Sriganesh

AU - Blasko, Adrienn

AU - Li, Xiaodun

AU - Aparicio, Samuel

AU - Tavaré, Simon

AU - OCCAMS Consortium

AU - Nowicki-Osuch, Karol

AU - Fitzgerald, Rebecca C.

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A2 - Loreno, Christine

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A2 - Freeman, Adam

A2 - Smyth, Elizabeth C.

A2 - O’Donovan, Maria

A2 - Miremadi, Ahmad

A2 - Malhotra, Shalini

A2 - Tripathi, Monika

A2 - Cheah, Calvin

A2 - Coles, Hannah

A2 - Millington, Curtis

A2 - Eldridge, Matthew

A2 - Secrier, Maria

A2 - Jammula, Sriganesh

A2 - Davies, Jim

A2 - Crichton, Charles

A2 - Carroll, Nick

A2 - Hardwick, Richard H.

A2 - Safranek, Peter

A2 - Hindmarsh, Andrew

A2 - Sujendran, Vijayendran

A2 - Hayes, Stephen J.

A2 - Ang, Yeng

A2 - Sharrocks, Andrew

A2 - Preston, Shaun R.

A2 - Bagwan, Izhar

A2 - Save, Vicki

A2 - Skipworth, Richard J.E.

A2 - Walker, Robert C.

A2 - Hanna, George B.

A2 - Petty, Russell D.

PY - 2024/5/14

Y1 - 2024/5/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85193207180

U2 - 10.1038/s41467-024-47619-4

DO - 10.1038/s41467-024-47619-4

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AN - SCOPUS:85193207180

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 4074

ER -

Disentangling oncogenic amplicons in esophageal adenocarcinoma

Abstract

UN SDGs

ASJC Scopus subject areas

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Author Correction: Disentangling oncogenic amplicons in esophageal adenocarcinoma (Nature Communications, (2024), 15, 1, (4074), 10.1038/s41467-024-47619-4)

Cite this