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Sci Rep. 2017 Jan 23;7:41071. doi: 10.1038/srep41071.

Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
2
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
3
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
4
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
5
Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
6
Department of Haematology, Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne, UK.
7
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
8
Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, UK.
9
Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK.
10
Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
11
Cardiff and Vale National Health Service Trust, Heath Park, Cardiff, UK.
12
Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
13
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
14
Centre for Primary Health Care Research, Lund University, Malmö, Sweden.
15
Institute of Human Genetics, University of Bonn, Germany.
16
Division of Medical Genetics, Department of Biomedicine, University of Basel, Switzerland.
17
Department of Genomics, Life &Brain Center, University of Bonn, Germany.
18
University of Duisburg-Essen, Essen, Germany.
19
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
20
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
21
National Center of Tumor Diseases, Heidelberg, Germany.

Abstract

B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.

PMID:
28112199
PMCID:
PMC5253627
DOI:
10.1038/srep41071
[Indexed for MEDLINE]
Free PMC Article

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