Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas
Alvin Wei Tian Ng, Gianmarco Contino, Sarah Killcoyne, Ginny Devonshire, Ray T. Hsu, Sujath Abbas, Jing Su, Aisling M. Redmond, Jamie Weaver, Matthew Eldridge, Simon Tavaré, Nicola Grehan, Barbara Nutzinger, Elwira Fidziukiewicz, Adam Freeman, Elizabeth Smyth, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Calvin Cheah, Hannah Coles, Connor Flint, Matthew Eldridge, Maria Secrier, Sriganesh Jammula, Jim Davies, Charles Crichton, Nick Carroll, Richard Hardwick, Peter Safranek, Andrew Hindmarsh, Vijayendran Sujendran, Stephen J. Hayes, Yeng Ang, Andrew D Sharrocks, Shaun R. Preston, Izhar Bagwan, Vicki Save, Richard J.E. Skipworth, Ted R. Hupp, J. Robert O’Neill, Olga Tucker, Andrew D. Beggs, Philippe Tanière, Sonia Puig, Tim Underwood, Robert Walker, Ben Grace, Jesper Lagergren, James Gossage, Andrew Davies, Fuju Chang, Ula Mahadeva, Vicky Goh, Francesca D. Ciccarelli, Grant Sanders, Richard Berrisford, David Tsz Chung Chan, Ed Cheong, Bhaskar Kumar, L. Sreedharan, Simon L. Parsons, Irshad Soomro, Philip Kaye, John Saunders, Laurence Lovat, Rehan Haidry, Michael Scott, Sharmila Sothi, Suzy Lishman, George B. Hanna, Christopher J. Peters, Krishna Moorthy, Anna M. Grabowska, Richard Turkington, Damian McManus, Helen G. Coleman, Russell Petty, Freddie Bartlett, Paul A. Edwards, Rebecca C. Fitzgerald
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.