Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

Abstract

The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia.

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Authors/Creators:	Robbe, P. https://orcid.org/0000-0002-0691-1126 Ridout, K.E. Vavoulis, D.V. https://orcid.org/0000-0002-3984-1507 Dréau, H. Kinnersley, B. https://orcid.org/0000-0003-1783-6296 Denny, N. https://orcid.org/0000-0002-5351-9581 Chubb, D. Appleby, N. https://orcid.org/0000-0001-5063-9652 Cutts, A. Cornish, A.J. https://orcid.org/0000-0002-3966-3501 Lopez-Pascua, L. Clifford, R. Burns, A. Stamatopoulos, B. Cabes, M. Alsolami, R. Antoniou, P. Oates, M. Cavalieri, D. Ambrose, J.C. Arumugam, P. Bevers, R. Bleda, M. Boardman-Pretty, F. Boustred, C.R. Brittain, H. Brown, M.A. Caulfield, M.J. Chan, G.C. Fowler, T. Giess, A. Hamblin, A. Henderson, S. Hubbard, T.J.P. Jackson, R. Jones, L.J. Kasperaviciute, D. Kayikci, M. Kousathanas, A. Lahnstein, L. Leigh, S.E.A. Leong, I.U.S. Lopez, F.J. Maleady-Crowe, F. McEntagart, M. Minneci, F. Moutsianas, L. Mueller, M. Murugaesu, N. Need, A.C. O’Donovan, P. Odhams, C.A. Patch, C. Perez-Gil, D. Pereira, M.B. Pullinger, J. Rahim, T. Rendon, A. Rogers, T. Savage, K. Sawant, K. Scott, R.H. Siddiq, A. Sieghart, A. Smith, S.C. Sosinsky, A. Stuckey, A. Tanguy, M. Taylor Tavares, A.L. Thomas, E.R.A. Thompson, S.R. Tucci, A. Welland, M.J. Williams, E. Witkowska, K. Wood, S.M. Allan, J. Bisshopp, G. Blakemore, S. Boultwood, J. Bruce, D. Buffa, F. Buggins, A. Cohen, G. Cwynarski, K. Dearden, C. Dillon, R. Ennis, S. Falciani, F. Follows, G. Forconi, F. Forster, J. Fox, C. Gribben, J. Hockaday, A. Howard, D. Jackson, A. Kalakonda, N. Khan, U. Law, P. Lefevre, P. Lin, K. Maseno, S. Moss, P. Packham, G. Palles, C. Parker, H. Patten, P. Pellagatti, A. Pratt, G. Ramsay, A. Rawstron, A. https://orcid.org/0000-0003-0798-9790 Rose-Zerilli, M. Slupsky, J. Stankovic, T. Steele, A. Strefford, J. Varadarajan, S. Vavoulis, D.V. Wagner, S. Westhead, D. https://orcid.org/0000-0002-0519-3820 Wordsworth, S. Zhuang, J. Gibson, J. https://orcid.org/0000-0002-0973-8285 Prabhu, A.V. Schwessinger, R. Jennings, D. James, T. Maheswari, U. Duran-Ferrer, M. https://orcid.org/0000-0003-1666-5819 Carninci, P. Knight, S.J.L. Månsson, R. Hughes, J. https://orcid.org/0000-0002-8955-7256 Davies, J. Ross, M. Bentley, D. Strefford, J.C. https://orcid.org/0000-0002-0972-2881 Devereux, S. https://orcid.org/0000-0002-8046-0386 Pettitt, A.R. Hillmen, P. Caulfield, M.J. Houlston, R.S. https://orcid.org/0000-0002-5268-0242 Martín-Subero, J.I. Schuh, A. https://orcid.org/0000-0002-3938-8490
Copyright, Publisher and Additional Information:	© The Author(s) 2022. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
Dates:	Accepted: 16 September 2022 Published (online): 4 November 2022 Published: 4 November 2022
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Clinical Trials Research (LICTR) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	17 Jul 2023 10:31
Last Modified:	17 Jul 2023 10:31
Status:	Published
Publisher:	Nature Research
Identification Number:	https://doi.org/10.1038/s41588-022-01211-y
Related URLs:	Author

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Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

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