Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features
Pauline Robbe, Kate Ridout, Dimitrios V. Vavoulis, Hélène Dreau, Ben Kinnersley, Nicholas Denny, Daniel Chubb, Niamh Appleby, Anthony Cutts, Alex J. Cornish, Laura Lopez-Pascua, Ruth Clifford, Adam Burns, Basile Stamatopoulos, Maité Cabes, Reem Alsolami, Pavlos Antoniou, Melanie Oates, Doriane Cavalieri, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Matthew A. Brown, M. J. Caulfield, G. C. Chan, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, F. J. Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Augusto Rendon, T. Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Sean Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, Eleanor Williams, Katarzyna Witkowska, Scott Wood, James M. Allan, Garry Bisshopp, Stuart J. Blakemore, Jacqueline Boultwood, David Bruce, Francesca M. Buffa, Andrea G.S. Buggins, Gerald M. Cohen, Kate Cwynarski, Claire Dearden, Richard Dillon, Sarah Ennis, Francesco Falciani, George Follows, Francesco Forconi, Jade Forster, Christopher P. Fox, John G. Gribben, Anna Hockaday, Dena Howard, Andrew Jackson, Nagesh Kalakonda, Umair Khan, Philip Law
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.