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; OCCAMS Consortium; Paul A. W. Edwards; Rebecca C. Fitzgerald

doi:10.1038/s42003-022-03238-7

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, OCCAMS Consortium, Paul A. W. Edwards, Rebecca C. Fitzgerald (Lead / Corresponding author)

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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 language	English
Article number	335
Number of pages	12
Journal	Communications Biology
Volume	5
Issue number	1
Early online date	8 Apr 2022
DOIs	https://doi.org/10.1038/s42003-022-03238-7
Publication status	Published - Dec 2022

ASJC Scopus subject areas

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

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Final published versionFinal published version, 5.16 MBLicence: CC BY

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Ng, A. W. T., Contino, G., Killcoyne, S., Devonshire, G., Hsu, R., Abbas, S., Su, J., Redmond, A. M., Weaver, J. M. J., Eldridge, M. D., Tavaré, S., OCCAMS Consortium, Edwards, P. A. W., & Fitzgerald, R. C. (2022). Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas. Communications Biology, 5(1), Article 335. https://doi.org/10.1038/s42003-022-03238-7

@article{ea8070a0a64840df998026694ae33b5e,

title = "Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas",

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.",

author = "Ng, {Alvin Wei Tian} and Gianmarco Contino and Sarah Killcoyne and Ginny Devonshire and Ray Hsu and Sujath Abbas and Jing Su and Redmond, {Aisling M.} and Weaver, {Jamie M.J.} and Eldridge, {Matthew D.} and Simon Tavar{\'e} and {OCCAMS Consortium} and Nicola Grehan and Barbara Nutzinger and Elwira Fidziukiewicz 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 Connor Flint 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 Hupp, {Ted R.} and O{\textquoteright}Neill, {J. Robert} and Olga Tucker and Andrew Beggs and Philippe Taniere and Sonia Puig and Underwood, {Timothy J.} and Walker, {Robert C.} and Grace, {Ben L.} and Jesper Lagergren and Gossage, {James A.} and Davies, {Andrew R.} and Fuju Chang and Ula Mahadeva and Vicky Goh and Ciccarelli, {Francesca D.} and Grant Sanders and Richard Berrisford and David Chan and Ed Cheong and Bhaskar Kumar and L. Sreedharan and Parsons, {Simon L.} and Soomro, {Irshad N.} and Philip Kaye and John Saunders and Laurence Lovat and Rehan Haidry and Michael Scott and Sharmila Sothi and Suzy Lishman and Hanna, {George B} and Peters, {Christopher J.} and Krishna Moorthy and Anna Grabowska and Richard Turkington and Damian McManus and Coleman, {Helen G.} and Russell Petty and Freddie Bartlett and Edwards, {Paul A. W.} and Fitzgerald, {Rebecca C.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03238-7",

language = "English",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

Ng, AWT, Contino, G, Killcoyne, S, Devonshire, G, Hsu, R, Abbas, S, Su, J, Redmond, AM, Weaver, JMJ, Eldridge, MD, Tavaré, S, OCCAMS Consortium, Edwards, PAW & Fitzgerald, RC 2022, 'Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas', Communications Biology, vol. 5, no. 1, 335. https://doi.org/10.1038/s42003-022-03238-7

TY - JOUR

T1 - Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas

AU - Ng, Alvin Wei Tian

AU - Contino, Gianmarco

AU - Killcoyne, Sarah

AU - Devonshire, Ginny

AU - Hsu, Ray

AU - Abbas, Sujath

AU - Su, Jing

AU - Redmond, Aisling M.

AU - Weaver, Jamie M.J.

AU - Eldridge, Matthew D.

AU - Tavaré, Simon

AU - OCCAMS Consortium

AU - Grehan, Nicola

AU - Nutzinger, Barbara

AU - Fidziukiewicz, Elwira

AU - Freeman, Adam

AU - Smyth, Elizabeth C.

AU - O’Donovan, Maria

AU - Miremadi, Ahmad

AU - Malhotra, Shalini

AU - Tripathi, Monika

AU - Cheah, Calvin

AU - Coles, Hannah

AU - Flint, Connor

AU - Eldridge, Matthew

AU - Secrier, Maria

AU - Jammula, Sriganesh

AU - Davies, Jim

AU - Crichton, Charles

AU - Carroll, Nick

AU - Hardwick, Richard H.

AU - Safranek, Peter

AU - Hindmarsh, Andrew

AU - Sujendran, Vijayendran

AU - Hayes, Stephen J.

AU - Ang, Yeng

AU - Sharrocks, Andrew

AU - Preston, Shaun R.

AU - Bagwan, Izhar

AU - Save, Vicki

AU - Skipworth, Richard J.E.

AU - Hupp, Ted R.

AU - O’Neill, J. Robert

AU - Tucker, Olga

AU - Beggs, Andrew

AU - Taniere, Philippe

AU - Puig, Sonia

AU - Underwood, Timothy J.

AU - Walker, Robert C.

AU - Grace, Ben L.

AU - Lagergren, Jesper

AU - Gossage, James A.

AU - Davies, Andrew R.

AU - Chang, Fuju

AU - Mahadeva, Ula

AU - Goh, Vicky

AU - Ciccarelli, Francesca D.

AU - Sanders, Grant

AU - Berrisford, Richard

AU - Chan, David

AU - Cheong, Ed

AU - Kumar, Bhaskar

AU - Sreedharan, L.

AU - Parsons, Simon L.

AU - Soomro, Irshad N.

AU - Kaye, Philip

AU - Saunders, John

AU - Lovat, Laurence

AU - Haidry, Rehan

AU - Scott, Michael

AU - Sothi, Sharmila

AU - Lishman, Suzy

AU - Hanna, George B

AU - Peters, Christopher J.

AU - Moorthy, Krishna

AU - Grabowska, Anna

AU - Turkington, Richard

AU - McManus, Damian

AU - Coleman, Helen G.

AU - Petty, Russell

AU - Bartlett, Freddie

AU - Edwards, Paul A. W.

AU - Fitzgerald, Rebecca C.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85127912804&partnerID=8YFLogxK

U2 - 10.1038/s42003-022-03238-7

DO - 10.1038/s42003-022-03238-7

M3 - Article

C2 - 35396535

AN - SCOPUS:85127912804

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 335

ER -

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

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