Multicenter Study

. 2018 Dec 21;9(1):1.

doi: 10.1038/s41408-018-0162-8.

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Molly Went¹, Amit Sud², Helen Speedy², Nicola J Sunter³, Asta Försti^{4

5}, Philip J Law², David C Johnson⁶, Fabio Mirabella⁶, Amy Holroyd², Ni Li², Giulia Orlando², Niels Weinhold^{7

8}, Mark van Duin⁹, Bowang Chen⁴, Jonathan S Mitchell², Larry Mansouri¹⁰, Gunnar Juliusson¹¹, Karin E Smedby¹², Sandrine Jayne¹³, Aneela Majid¹³, Claire Dearden⁶, David J Allsup¹⁴, James R Bailey¹⁵, Guy Pratt¹⁶, Chris Pepper¹⁷, Chris Fegan¹⁸, Richard Rosenquist¹⁰, Rowan Kuiper⁹, Owen W Stephens⁷, Uta Bertsch^{4

19}, Peter Broderick², Hermann Einsele²⁰, Walter M Gregory²¹, Jens Hillengass⁸, Per Hoffmann^{22

23}, Graham H Jackson²⁴, Karl-Heinz Jöckel²⁵, Jolanta Nickel⁸, Markus M Nöthen^{22

26}, Miguel Inacio da Silva Filho⁴, Hauke Thomsen⁴, Brian A Walker⁷, Annemiek Broyl⁹, Faith E Davies⁷, Markus Hansson^{5

27}, Hartmut Goldschmidt^{8

19}, Martin J S Dyer¹³, Martin Kaiser⁶, Pieter Sonneveld⁹, Gareth J Morgan⁷, Kari Hemminki^{4

5}, Björn Nilsson^{27

28}, Daniel Catovsky⁶, James M Allan³, Richard S Houlston^{2

6}

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. molly.went@icr.ac.uk.
² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
³ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
⁴ German Cancer Research Center, 69120, Heidelberg, Germany.
⁵ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden.
⁶ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK.
⁷ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
⁸ Department of Internal Medicine V, University of Heidelberg, 69117, Heidelberg, Germany.
⁹ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, The Netherlands.
¹⁰ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
¹¹ Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Hematology and Transplantation, Lund University, Lund, Sweden.
¹² Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³ Ernest and Helen Scott Haematological Research Institute, Leicester University, Leicester, UK.
¹⁴ Department of Haematology, Hull Royal Infirmary, Hull, UK.
¹⁵ Hull York Medical School and University of Hull, Hull, UK.
¹⁶ Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK.
¹⁷ Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
¹⁸ Cardiff and Vale National Health Service Trust, Heath Park, Cardiff, UK.
¹⁹ National Centre of Tumor Diseases, 69120, Heidelberg, Germany.
²⁰ University Clinic of Würzburg, 97080, Würzburg, Germany.
²¹ Clinical Trials Research Unit, University of Leeds, Leeds, LS2 9PH, UK.
²² Institute of Human Genetics, University of Bonn, D-53127, Bonn, Germany.
²³ Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003, Basel, Switzerland.
²⁴ Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
²⁵ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Department of Genomics, Life and Brain Center, University of Bonn, D-53127, Bonn, Germany.
²⁷ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund University, Lund, Sweden.
²⁸ Broad Institute, 7 Cambridge Center, Cambridge, MA, 02142, USA.

PMID: 30602759
PMCID: PMC6315026
DOI: 10.1038/s41408-018-0162-8

Multicenter Study

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Molly Went et al. Blood Cancer J. 2018.

. 2018 Dec 21;9(1):1.

doi: 10.1038/s41408-018-0162-8.

Authors

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. molly.went@icr.ac.uk.
² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
³ Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
⁴ German Cancer Research Center, 69120, Heidelberg, Germany.
⁵ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden.
⁶ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK.
⁷ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
⁸ Department of Internal Medicine V, University of Heidelberg, 69117, Heidelberg, Germany.
⁹ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, The Netherlands.
¹⁰ Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105, Uppsala, Sweden.
¹¹ Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Hematology and Transplantation, Lund University, Lund, Sweden.
¹² Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³ Ernest and Helen Scott Haematological Research Institute, Leicester University, Leicester, UK.
¹⁴ Department of Haematology, Hull Royal Infirmary, Hull, UK.
¹⁵ Hull York Medical School and University of Hull, Hull, UK.
¹⁶ Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK.
¹⁷ Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
¹⁸ Cardiff and Vale National Health Service Trust, Heath Park, Cardiff, UK.
¹⁹ National Centre of Tumor Diseases, 69120, Heidelberg, Germany.
²⁰ University Clinic of Würzburg, 97080, Würzburg, Germany.
²¹ Clinical Trials Research Unit, University of Leeds, Leeds, LS2 9PH, UK.
²² Institute of Human Genetics, University of Bonn, D-53127, Bonn, Germany.
²³ Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003, Basel, Switzerland.
²⁴ Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
²⁵ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Department of Genomics, Life and Brain Center, University of Bonn, D-53127, Bonn, Germany.
²⁷ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund University, Lund, Sweden.
²⁸ Broad Institute, 7 Cambridge Center, Cambridge, MA, 02142, USA.

PMID: 30602759
PMCID: PMC6315026
DOI: 10.1038/s41408-018-0162-8

Abstract

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 (R_g = 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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Schematic outlining the processing of data sets used in the genetic correlation

**Fig. 2. Overlap of loci in multiple myeloma and chronic lymphocytic leukaemia.**
*correlated variants at 3q26.2 had been previously published as genome wide significant in each data set prior to this analysis

See this image and copyright information in PMC

References

1. Barlogie B, Gale RP. Multiple myeloma and chronic lymphocytic leukemia: parallels and contrasts. Am. J. Med. 1992;93:443–450. doi: 10.1016/0002-9343(92)90176-C. - DOI - PubMed
1. Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat. Rev. Immunol. 2002;2:920–932. doi: 10.1038/nri953. - DOI - PubMed
1. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer. 2005;5:251–262. doi: 10.1038/nrc1589. - DOI - PubMed
1. Sud, A., et al. The landscape of familial risk of hematological malignancies: an analysis of 153,115 cases. (Under review).
1. Crowther-Swanepoel D, et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 2010;42:132–136. doi: 10.1038/ng.510. - DOI - PMC - PubMed

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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Affiliations

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials