Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features
Authors: Robbe Pauline , Ridout Kate E. , Vavoulis Dimitrios V. , Dréau Helene , Kinnersley Ben , Denny Nicholas , Chubb Daniel , Appleby Niamh , Cutts Anthony , Cornish Alex J. , Lopez-Pascua Laura , Clifford Ruth , Burns Adam , Stamatopoulos Basile , Cabes Maite , Alsolami Reem , Antoniou Pavlos , Oates Melanie , Cavalieri Doriane ,   Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Bevers R. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Brown M. A. , Caulfield Marc 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 Alona , 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. ,   CLL pilot consortium, Allan James , Bisshopp Garry , Blakemore Stuart , Boultwood Jacqueline , Bruce David , Buffa Francesca , Buggins Andrea , Cohen Gerald , Cwynarski Kate , Dearden Claire , Dillon Richard , Ennis Sarah , Falciani Francesco , Follows George , Forconi Francesco , Forster Jade , Fox Christopher , Gribben John , Hockaday Anna , Howard Dena , Jackson Andrew , Kalakonda Nagesh , Khan Umair , Law Philip , Lefevre Pascal , Lin Ke , Maseno Sandra , Moss Paul , Packham Graham , Palles Claire , Parker Helen , Patten Piers , Pellagatti Andrea , Pratt Guy , Ramsay Alan , Rawstron Andy , Rose-Zerilli Matthew , Slupsky Joseph , Stankovic Tatjana , Steele Andrew , Strefford Jonathan , Varadarajan Shankar , Vavoulis Dimitrios V. , Wagner Simon , Westhead David , Wordsworth Sarah , Zhuang Jack , Gibson Jane , Prabhu Anika V. , Schwessinger Ron , Jennings Daisy , James Terena , Maheswari Uma , Duran-Ferrer Martí , Carninci Piero , Knight Samantha J. L. , Månsson Robert , Hughes Jim , Davies James , Ross Mark , Bentley David , Strefford Jonathan C. , Devereux Stephen , Pettitt Andrew R. , Hillmen Peter , Caulfield Mark J. , Houlston Richard S. , Martín-Subero José I. , Schuh Anna 
Published: November 2022

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.