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

Lin, Wei Yu; Fordham, Sarah E.; Sunter, Nicola; Elstob, Claire; Rahman, Thahira; Willmore, Elaine; Shepherd, Colin; Strathdee, Gordon; Mainou-Fowler, Tryfonia; Piddock, Rachel; Mearns, Hannah; Barrow, Timothy; Houlston, Richard S.; Marr, Helen; Wallis, Jonathan; Summerfield, Geoffrey; Marshall, Scott; Pettitt, Andrew; Pepper, Christopher; Fegan, Christopher; Forconi, Francesco; Dyer, Martin J.S.; Jayne, Sandrine; Sellors, April; Schuh, Anna; Robbe, Pauline; Oscier, David; Bailey, James; Rais, Syed; Bentley, Alison; Cawkwell, Lynn; Evans, Paul; Hillmen, Peter; Pratt, Guy; Allsup, David J.; Allan, James M.

Authors

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

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Dr David Allsup D.J.Allsup@hull.ac.uk
Senior Lecturer in Haematology and Honorary Consultant

James M. Allan



Abstract

© 2021, The Author(s). 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.

Citation

Lin, W. Y., Fordham, S. E., Sunter, N., Elstob, C., Rahman, T., Willmore, E., …Allan, J. M. (2021). Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia. Nature communications, 12(1), Article 665. https://doi.org/10.1038/s41467-020-20822-9

Journal Article Type Article
Acceptance Date Dec 16, 2020
Online Publication Date Jan 28, 2021
Publication Date 2021-12
Deposit Date Jan 28, 2021
Publicly Available Date Mar 28, 2024
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Article Number 665
DOI https://doi.org/10.1038/s41467-020-20822-9
Keywords Cancer genetics; Cancer genomics; Chronic lymphocytic leukaemia; Genetic markers; Prognostic markers
Public URL https://hull-repository.worktribe.com/output/3703447
Publisher URL https://www.nature.com/articles/s41467-020-20822-9

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Copyright Statement
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.





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