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.

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., Shepherd, C., Strathdee, G., Mainou-Fowler, T., Piddock, R., Mearns, H., Barrow, T., Houlston, R. S., Marr, H., Wallis, J., Summerfield, G., Marshall, S., Pettitt, A., Pepper, C., Fegan, C., …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: Feb 1, 2021
• 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