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

Lookup NU author(s): Dr Wei-Yu Lin, Dr Sarah FordhamORCiD, Dr Nicola Sunter, Dr Claire Elstob, Dr Thahira Rahman, Dr Elaine WillmoreORCiD, Dr Colin Shepherd, Dr Gordon Strathdee, Dr Tryfonia Mainou-Fowler, Dr Rachel PiddockORCiD, Dr Timothy Barrow, Dr Helen Marr, Professor James Allan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Lin W-Y, Fordham SE, Sunter N, Elstob C, Rahman T, Willmore E, Shepherd C, Strathdee G, Mainou-Fowler T, Piddock R, Mearns H, Barrow T, Houlston RS, Marr H, Wallis J, Summerfield G, Marshall S, Pettitt A, Pepper C, Fegan C, Forconi F, Dyer MJS, Jayne S, Sellors A, Schuh A, Robbe P, Oscier D, Bailey J, Rais S, Bentley A, Cawkwell L, Evans P, Hillmen P, Pratt G, Allsup DJ, Allan JM

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2021

Volume: 12

Issue: 1

Online publication date: 28/01/2021

Acceptance date: 16/12/2020

Date deposited: 31/03/2021

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-020-20822-9

DOI: 10.1038/s41467-020-20822-9


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Funding

Funder referenceFunder name
Blood Cancer UK (formely Bloodwise) (#06002 and #13044 to J.M.A.)
A.S. was partly funded by the National Institute for Health Research Oxford Biomedical Research Centre
E.W. and G.S. received funding from Blood Cancer UK (#14024)
C.E. received funding from JGW Patterson Foundation.
J.M.A. is recipient of an Oncology/Haematology Fellowship from Gilead Pharmaceuticals
supported by Cancer Research UK (C2115/A21421).

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