Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.pdf (796.11 kB)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

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posted on 15.08.2019, 13:40 by M Went, A Sud, H Speedy, NJ Sunter, A Försti, PJ Law, DC Johnson, F Mirabella, A Holroyd, N Li, G Orlando, N Weinhold, M van Duin, B Chen, JS Mitchell, L Mansouri, G Juliusson, KE Smedby, S Jayne, A Majid, C Dearden, DJ Allsup, JR Bailey, G Pratt, C Pepper, C Fegan, R Rosenquist, R Kuiper, OW Stephens, U Bertsch, P Broderick, H Einsele, WM Gregory, J Hillengass, P Hoffmann, GH Jackson, K-H Jöckel, J Nickel, MM Nöthen, MI da Silva Filho, H Thomsen, BA Walker, A Broyl, FE Davies, M Hansson, H Goldschmidt, MJS Dyer, M Kaiser, P Sonneveld, GJ Morgan, K Hemminki, B Nilsson, D Catovsky, JM Allan, RS Houlston
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Funding

In the United Kingdom, Myeloma UK and Bloodwise (#05001, #06002 and #13044) provided principal funding. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and The Rosetrees Trust. M.W. is supported by funding from Mr Ralph Stockwell. A.S. is supported by a clinical fellowship from Cancer Research UK and the Royal Marsden Haematology Research Fund. This study made use of genotyping data on the 1958 Birth Cohort generated by the Wellcome Trust Sanger Institute (http://www.wtccc.org.uk). We are grateful to all investigators who contributed to NSCCG and GELCAPS, from which controls in the replication were drawn. We also thank the staff of the CTRU University of Leeds and the NCRI Haematology Clinical Studies Group. We thank the High-throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of UK myeloma Oncoarray data. The BCAC study would not have been possible without the contributions of the following: Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou and Joe Dennis. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A16563). For the BBCS study, we thank Eileen Williams, Elaine Ryder-Mills and Kara Sargus. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the National Institute of Health Research (NIHR) Biomedical Research Centre (BRC), and the National Cancer Research Network (NCRN). We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German

History

Citation

Blood Cancer Journal, 2018, 9, Article number: 1

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

VoR (Version of Record)

Published in

Blood Cancer Journal

Publisher

Springer Nature

eissn

2044-5385

Acceptance date

19/11/2018

Copyright date

2018

Available date

15/08/2019

Publisher version

https://www.nature.com/articles/s41408-018-0162-8

Notes

Supplementary Information accompanies this paper at (https://doi.org/10.1038/s41408-018-0162-8).

Language

en

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