Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas

Alvin Wei Tian Ng, Gianmarco Contino, Sarah Killcoyne, Ginny Devonshire, Ray Hsu, Sujath Abbas, Jing Su, Aisling M. Redmond, Jamie M.J. Weaver, Matthew D. Eldridge, Simon Tavaré, Nicola Grehan, Barbara Nutzinger, Elwira Fidziukiewicz, Adam Freeman, Elizabeth C. Smyth, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika TripathiCalvin Cheah, Hannah Coles, Connor Flint, 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 J.E. Skipworth, Ted R. Hupp, J. Robert O’Neill, Olga Tucker, Andrew Beggs, Philippe Taniere, Sonia Puig, Michael Scott, Richard Turkington, Damian McManus, Helen Coleman, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium

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Abstract

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.

Original languageEnglish
Article number335
JournalCommunications Biology
Volume5
DOIs
Publication statusPublished - 08 Apr 2022

Bibliographical note

Funding Information:
We sincerely thank Jens Luebeck and Vineet Bafna (UCSD) on their help with Amplicon Architect and suggestions on the ecDNA analysis. We sincerely thank Sonia Zumalave and Jose Tubio (USC) on their kind help to run the TraFic workflow and comments on the manuscript. We thank the Human Research Tissue Bank, which is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119).

Funding Information:
We sincerely thank Jens Luebeck and Vineet Bafna (UCSD) on their help with Amplicon Architect and suggestions on the ecDNA analysis. We sincerely thank Sonia Zumalave and Jose Tubio (USC) on their kind help to run the TraFic workflow and comments on the manuscript. We thank the Human Research Tissue Bank, which is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119).

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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