Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia

Wei-Yu Lin, Sarah E. Fordham, Nicola Sunter, Claire Elstob, Thahira Rahman, Elaine Willmore, Colin Shepherd, Gordon Strathdee, Tryfonia Mainou-Fowler, Rachel Piddock, Hannah Mearns, Timothy Barrow, Richard S. Houlston, Helen Marr, Jonathan Wallis, Geoffrey Summerfield, Scott Marshall, Andrew Pettitt, Christopher Pepper, Christopher Fegan, Francesco Forconi, Martin J. S. Dyer, Sandrine Jayne, April Sellors, Anna Schuh, Pauline Robbe, David Oscier, James Bailey, Syed Rais, Alison Bentley, Lynn Cawkwell, Paul Evans, Peter Hillmen, Guy Pratt, David J. Allsup () and James M. Allan ()
Additional contact information
Wei-Yu Lin: Newcastle University
Sarah E. Fordham: Newcastle University
Nicola Sunter: Newcastle University
Claire Elstob: Newcastle University
Thahira Rahman: Newcastle University
Elaine Willmore: Newcastle University
Colin Shepherd: Newcastle University
Gordon Strathdee: Newcastle University
Tryfonia Mainou-Fowler: Newcastle University
Rachel Piddock: Newcastle University
Hannah Mearns: Newcastle University
Timothy Barrow: University of Sunderland
Richard S. Houlston: The Institute of Cancer Research
Helen Marr: Freeman Hospital
Jonathan Wallis: Freeman Hospital
Geoffrey Summerfield: Queen Elizabeth Hospital
Scott Marshall: City Hospitals Sunderland NHS Trust
Andrew Pettitt: University of Liverpool
Christopher Pepper: University of Sussex
Christopher Fegan: Cardiff University
Francesco Forconi: University of Southampton
Martin J. S. Dyer: University of Leicester
Sandrine Jayne: University of Leicester
April Sellors: University of Leicester
Anna Schuh: University of Oxford
Pauline Robbe: University of Oxford
David Oscier: Royal Bournemouth Hospital
James Bailey: Hull University Teaching Hospital NHS Trust
Syed Rais: Hull University Teaching Hospital NHS Trust
Alison Bentley: Hull York Medical School
Lynn Cawkwell: University of Hull
Paul Evans: St James’ Institute of Oncology
Peter Hillmen: Leeds Institute of Medical Research at St James’s, University of Leeds
Guy Pratt: University of Birmingham
David J. Allsup: Hull University Teaching Hospital NHS Trust
James M. Allan: Newcastle University

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: Abstract Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47–2.15; P = 2.71 × 10−9) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55–2.55; P = 5.08 × 10−8), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.

Date: 2021
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DOI: 10.1038/s41467-020-20822-9

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