Disentangling oncogenic amplicons in esophageal adenocarcinoma
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 w...
Main Authors: | , , , , , , , , , , , , , , , , , |
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Format: | Journal Article |
Language: | English |
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2024
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Online Access: | https://hdl.handle.net/10356/179745 |
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author | Ng, Alvin Wei Tian McClurg, Dylan Peter Wesley, Ben Zamani, Shahriar A. Black, Emily Miremadi, Ahmad Giger, Olivier Hoopen, Rogier Ten Devonshire, Ginny Redmond, Aisling M. Grehan, Nicola Jammula, Sriganesh Blasko, Adrienn Li, Xiaodun Aparicio, Samuel Tavaré, Simon Nowicki-Osuch, Karol Fitzgerald, Rebecca C. |
author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Ng, Alvin Wei Tian McClurg, Dylan Peter Wesley, Ben Zamani, Shahriar A. Black, Emily Miremadi, Ahmad Giger, Olivier Hoopen, Rogier Ten Devonshire, Ginny Redmond, Aisling M. Grehan, Nicola Jammula, Sriganesh Blasko, Adrienn Li, Xiaodun Aparicio, Samuel Tavaré, Simon Nowicki-Osuch, Karol Fitzgerald, Rebecca C. |
author_sort | Ng, Alvin Wei Tian |
collection | NTU |
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. |
first_indexed | 2024-10-01T04:43:35Z |
format | Journal Article |
id | ntu-10356/179745 |
institution | Nanyang Technological University |
language | English |
last_indexed | 2024-10-01T04:43:35Z |
publishDate | 2024 |
record_format | dspace |
spelling | ntu-10356/1797452024-08-25T15:38:18Z Disentangling oncogenic amplicons in esophageal adenocarcinoma Ng, Alvin Wei Tian McClurg, Dylan Peter Wesley, Ben Zamani, Shahriar A. Black, Emily Miremadi, Ahmad Giger, Olivier Hoopen, Rogier Ten Devonshire, Ginny Redmond, Aisling M. Grehan, Nicola Jammula, Sriganesh Blasko, Adrienn Li, Xiaodun Aparicio, Samuel Tavaré, Simon Nowicki-Osuch, Karol Fitzgerald, Rebecca C. Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Adenocarcinoma Clonal evolution 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. Published version The laboratory of R.C.F is supported by a Program Grant from the Medical Research Council (MR/W014122/1). This work was supported by Cancer Research UK (A15874, A22720, A22131). SAZ is supported by a Gates-Cambridge Trust scholarship. We thank the Human Research Tissue Bank, which is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Center, from Addenbrooke’s Hospital. This research was supported by the NIHR Cambridge Biomedical Research Center (NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. S.T. and K.N.O. were funded by the MacMillan Family Foundation (60210014) as part of the MacMillan Center for the Study of the Non-Coding Cancer Genome at the New York Genome Center including B.W.’s studentship. 2024-08-20T05:50:06Z 2024-08-20T05:50:06Z 2024 Journal Article 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., Nowicki-Osuch, K. & Fitzgerald, R. C. (2024). Disentangling oncogenic amplicons in esophageal adenocarcinoma. Nature Communications, 15(1), 4074-. https://dx.doi.org/10.1038/s41467-024-47619-4 2041-1723 https://hdl.handle.net/10356/179745 10.1038/s41467-024-47619-4 38744814 2-s2.0-85193207180 1 15 4074 en Nature Communications © The Author(s) 2024, corrected publication 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |
spellingShingle | Medicine, Health and Life Sciences Adenocarcinoma Clonal evolution Ng, Alvin Wei Tian McClurg, Dylan Peter Wesley, Ben Zamani, Shahriar A. Black, Emily Miremadi, Ahmad Giger, Olivier Hoopen, Rogier Ten Devonshire, Ginny Redmond, Aisling M. Grehan, Nicola Jammula, Sriganesh Blasko, Adrienn Li, Xiaodun Aparicio, Samuel Tavaré, Simon Nowicki-Osuch, Karol Fitzgerald, Rebecca C. Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title | Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title_full | Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title_fullStr | Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title_full_unstemmed | Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title_short | Disentangling oncogenic amplicons in esophageal adenocarcinoma |
title_sort | disentangling oncogenic amplicons in esophageal adenocarcinoma |
topic | Medicine, Health and Life Sciences Adenocarcinoma Clonal evolution |
url | https://hdl.handle.net/10356/179745 |
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