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

Genomics England Research Consortium; CLL pilot consortium; Jane Gibson; Anika V. Prabhu; Ron Schwessinger; Daisy Jennings; Terena James; Uma Maheswari; Martí Duran-Ferrer; Piero Carninci; Samantha J. L. Knight; Robert Månsson; Jim Hughes; James Davies; Mark Ross; David Bentley; Jonathan C Strefford; Stephen Devereux; Andrew R. Pettitt; Peter Hillmen; Mark J. Caulfield; Richard S. Houlston; José I. Martín-Subero; Anna Schuh; Christopher Fox; Paul Moss; Claire Palles; Guy Pratt; Tatjana Stankovic

doi:10.1038/s41588-022-01211-y

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

Genomics England Research Consortium, CLL pilot consortium, Jane Gibson, Anika V. Prabhu, Ron Schwessinger, Daisy Jennings, Terena James, Uma Maheswari, Martí Duran-Ferrer, Piero Carninci, Samantha J. L. Knight, Robert Månsson, Jim Hughes, James Davies, Mark Ross, David Bentley, Jonathan C Strefford, Stephen Devereux, Andrew R. Pettitt, Peter HillmenMark J. Caulfield, Richard S. Houlston, José I. Martín-Subero, Anna Schuh^*, Christopher Fox, Paul Moss, Claire Palles, Guy Pratt, Tatjana Stankovic

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	1675-1689
Number of pages	15
Journal	Nature Genetics
Volume	54
Issue number	11
DOIs	https://doi.org/10.1038/s41588-022-01211-y
Publication status	Published - 4 Nov 2022

Bibliographical note

Funding Information:
In the past five years, A.S. has received in-kind contributions from Illumina and Oxford Nanopore Technology and is a shareholder of Illumina. She is a company director and shareholder of SERENOx Ltd. A.S. has received honoraria from Exact Sciences, Janssen, Astra Zeneca, Abbvie and Beigene, non-restricted research grants from Janssen and Astra Zeneca and an educational grant from Abbvie. A.R.P. receives research funding from Celgene/BMS, Gilead, Napp and Roche. N.A. received speaker fees from Gilead. P.A., T.J., U.M., M.R. and D.B. are employees of Illumina, a public company that develops and markets systems for genetic analysis. The remaining authors declare no competing interests.

Patient material was obtained from the UK CLL Biobank, University of Liverpool, which is funded by Blood Cancer UK. This work was supported by the Genomics England Research Consortium and the CLL pilot consortium (full list of Individual consortia authors are listed in the ). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This work was supported by the National Institute for Health Research Oxford Biomedical Research Centre (A.S., D.V. and K.R.). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The work of P.R. was supported by the Japan Society for the Promotion of Science Postdoctoral standard program. The work of R.S.H. is supported Wellcome Trust (214388) and Cancer Research UK (C124388) grants. The work of A.R.P. and S.D. was supported by Blood Cancer UK. A.B. received D.Phil. funding from Health Education England and Genomics England. J.I.M.-S. is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (Project BCLLATLAS, grant agreement 810287). J.C.S. is funded by Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087 and program C2750/A23669). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Genomics England Research Consortium, CLL pilot consortium, Gibson, J., Prabhu, A. V., Schwessinger, R., Jennings, D., James, T., Maheswari, U., Duran-Ferrer, M., Carninci, P., Knight, S. J. L., Månsson, R., Hughes, J., Davies, J., Ross, M., Bentley, D., Strefford, J. C., Devereux, S., Pettitt, A. R., ... Stankovic, T. (2022). Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features. Nature Genetics, 54(11), 1675-1689. https://doi.org/10.1038/s41588-022-01211-y

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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{\textquoteright}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.",

author = "{Genomics England Research Consortium} and {CLL pilot consortium} and Pauline Robbe and Ridout, {Kate E.} and Vavoulis, {Dimitrios V.} and Helene Dr{\'e}au and Ben Kinnersley and Nicholas Denny and Daniel Chubb and Niamh Appleby and Anthony Cutts and Cornish, {Alex J.} and Laura Lopez-Pascua and Ruth Clifford and Adam Burns and Basile Stamatopoulos and Maite Cabes and Reem Alsolami and Pavlos Antoniou and Melanie Oates and Doriane Cavalieri and Jane Gibson and Prabhu, {Anika V.} and Ron Schwessinger and Daisy Jennings and Terena James and Uma Maheswari and Mart{\'i} Duran-Ferrer and Piero Carninci and Knight, {Samantha J. L.} and Robert M{\aa}nsson and Jim Hughes and James Davies and Mark Ross and David Bentley and Strefford, {Jonathan C} and Stephen Devereux and Pettitt, {Andrew R.} and Peter Hillmen and Caulfield, {Mark J.} and Houlston, {Richard S.} and Mart{\'i}n-Subero, {Jos{\'e} I.} and Anna Schuh and Christopher Fox and Paul Moss and Claire Palles and Guy Pratt and Tatjana Stankovic",

note = "Funding Information: In the past five years, A.S. has received in-kind contributions from Illumina and Oxford Nanopore Technology and is a shareholder of Illumina. She is a company director and shareholder of SERENOx Ltd. A.S. has received honoraria from Exact Sciences, Janssen, Astra Zeneca, Abbvie and Beigene, non-restricted research grants from Janssen and Astra Zeneca and an educational grant from Abbvie. A.R.P. receives research funding from Celgene/BMS, Gilead, Napp and Roche. N.A. received speaker fees from Gilead. P.A., T.J., U.M., M.R. and D.B. are employees of Illumina, a public company that develops and markets systems for genetic analysis. The remaining authors declare no competing interests. Patient material was obtained from the UK CLL Biobank, University of Liverpool, which is funded by Blood Cancer UK. This work was supported by the Genomics England Research Consortium and the CLL pilot consortium (full list of Individual consortia authors are listed in the ). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This work was supported by the National Institute for Health Research Oxford Biomedical Research Centre (A.S., D.V. and K.R.). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The work of P.R. was supported by the Japan Society for the Promotion of Science Postdoctoral standard program. The work of R.S.H. is supported Wellcome Trust (214388) and Cancer Research UK (C124388) grants. The work of A.R.P. and S.D. was supported by Blood Cancer UK. A.B. received D.Phil. funding from Health Education England and Genomics England. J.I.M.-S. is funded by the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation program (Project BCLLATLAS, grant agreement 810287). J.C.S. is funded by Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087 and program C2750/A23669). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022, The Author(s). ",

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doi = "10.1038/s41588-022-01211-y",

language = "English",

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Genomics England Research Consortium, CLL pilot consortium, Gibson, J, Prabhu, AV, Schwessinger, R, Jennings, D, James, T, Maheswari, U, Duran-Ferrer, M, Carninci, P, Knight, SJL, Månsson, R, Hughes, J, Davies, J, Ross, M, Bentley, D, Strefford, JC, Devereux, S, Pettitt, AR, Hillmen, P, Caulfield, MJ, Houlston, RS, Martín-Subero, JI, Schuh, A, Fox, C, Moss, P , Palles, C, Pratt, G & Stankovic, T 2022, 'Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features', Nature Genetics, vol. 54, no. 11, pp. 1675-1689. https://doi.org/10.1038/s41588-022-01211-y

TY - JOUR

T1 - Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

AU - Genomics England Research Consortium

AU - CLL pilot consortium

AU - Robbe, Pauline

AU - Ridout, Kate E.

AU - Vavoulis, Dimitrios V.

AU - Dréau, Helene

AU - Kinnersley, Ben

AU - Denny, Nicholas

AU - Chubb, Daniel

AU - Appleby, Niamh

AU - Cutts, Anthony

AU - Cornish, Alex J.

AU - Lopez-Pascua, Laura

AU - Clifford, Ruth

AU - Burns, Adam

AU - Stamatopoulos, Basile

AU - Cabes, Maite

AU - Alsolami, Reem

AU - Antoniou, Pavlos

AU - Oates, Melanie

AU - Cavalieri, Doriane

AU - Gibson, Jane

AU - Prabhu, Anika V.

AU - Schwessinger, Ron

AU - Jennings, Daisy

AU - James, Terena

AU - Maheswari, Uma

AU - Duran-Ferrer, Martí

AU - Carninci, Piero

AU - Knight, Samantha J. L.

AU - Månsson, Robert

AU - Hughes, Jim

AU - Davies, James

AU - Ross, Mark

AU - Bentley, David

AU - Strefford, Jonathan C

AU - Devereux, Stephen

AU - Pettitt, Andrew R.

AU - Hillmen, Peter

AU - Caulfield, Mark J.

AU - Houlston, Richard S.

AU - Martín-Subero, José I.

AU - Schuh, Anna

AU - Fox, Christopher

AU - Moss, Paul

AU - Palles, Claire

AU - Pratt, Guy

AU - Stankovic, Tatjana

N1 - Funding Information: In the past five years, A.S. has received in-kind contributions from Illumina and Oxford Nanopore Technology and is a shareholder of Illumina. She is a company director and shareholder of SERENOx Ltd. A.S. has received honoraria from Exact Sciences, Janssen, Astra Zeneca, Abbvie and Beigene, non-restricted research grants from Janssen and Astra Zeneca and an educational grant from Abbvie. A.R.P. receives research funding from Celgene/BMS, Gilead, Napp and Roche. N.A. received speaker fees from Gilead. P.A., T.J., U.M., M.R. and D.B. are employees of Illumina, a public company that develops and markets systems for genetic analysis. The remaining authors declare no competing interests. Patient material was obtained from the UK CLL Biobank, University of Liverpool, which is funded by Blood Cancer UK. This work was supported by the Genomics England Research Consortium and the CLL pilot consortium (full list of Individual consortia authors are listed in the ). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This work was supported by the National Institute for Health Research Oxford Biomedical Research Centre (A.S., D.V. and K.R.). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The work of P.R. was supported by the Japan Society for the Promotion of Science Postdoctoral standard program. The work of R.S.H. is supported Wellcome Trust (214388) and Cancer Research UK (C124388) grants. The work of A.R.P. and S.D. was supported by Blood Cancer UK. A.B. received D.Phil. funding from Health Education England and Genomics England. J.I.M.-S. is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (Project BCLLATLAS, grant agreement 810287). J.C.S. is funded by Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087 and program C2750/A23669). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2022, The Author(s).

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Y1 - 2022/11/4

N2 - 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.

AB - 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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JF - Nature Genetics

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ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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