TY - JOUR
T1 - Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas
AU - Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
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 - 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 - Chan, David
N1 - Publisher Copyright:
© 2022, The Author(s).
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 - https://www.scopus.com/pages/publications/85127912804
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 -