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Nat Commun. 2018 Oct 10;9(1):4182. doi: 10.1038/s41467-018-06541-2.

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA. Mary.McMaster@nih.hhs.gov.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA.
3
Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 35233, AL, USA.
4
Department of Health Sciences Research, Mayo Clinic, Rochester, 55905, MN, USA.
5
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Lab for Cancer Research, Frederick, 20877, MD, USA.
6
Centre for Big Data Research in Health, University of New South Wales, Sydney, 2052, NSW, Australia.
7
Department of Medicine, Solna Karolinska Institutet, Stockholm, 17176, Sweden.
8
Hematology Center, Karolinska University Hospital, Stockholm, 17176, Sweden.
9
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
10
Department of Pathology, University of Alabama at Birmingham, Birmingham, 35233, AL, USA.
11
Department of Health Sciences, University of York, York, YO10 5DD, UK.
12
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Graduate College, New York, 10021, NY, USA.
13
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
14
Department of Statistics, Dongguk University, Seoul, 100-715, Republic of Korea.
15
Epidemiology Research Program, American Cancer Society, Atlanta, 30303, GA, USA.
16
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
17
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
18
Institute of Health and Society, Clinical Effectiveness Research Group, University of Oslo, Oslo, NO-0316, Norway.
19
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, 94118, CA, USA.
20
International Agency for Research on Cancer (IARC), Lyon, 69372, France.
21
Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, F-94807, France.
22
Université Paris Descartes, Paris, 75006, France.
23
Registry of Hematological Malignancies in Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, Bordeaux, 33000, France.
24
Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, 52242, IA, USA.
25
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, 3508 TD, The Netherlands.
26
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
27
Department of Internal Medicine, Mayo Clinic, Rochester, 55905, MN, USA.
28
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
29
Division of Health Surveillance and Research, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2300, Denmark.
30
Department of Medicine, Stanford University School of Medicine, Stanford, 94305, CA, USA.
31
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
32
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
33
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
34
Service d'hématologie et Oncologie, Centre Hospitalier de Versailles, Le Chesnay, Inserm U1018, Centre pour la Recherche en Epidémiologie et Santé des Populations (CESP), Villejuif, 78157, France.
35
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
36
Cancer Epidemiology Unit, University of Oxford, Oxford, OX3 7LF, UK.
37
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK.
38
Human Genetics Foundation, Turin, 10126, Italy.
39
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, 9019, Norway.
40
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, 0379, Norway.
41
Genetic Epidemiology Group, Folkhälsan Research Center and University of Helsinki, Helsinki, 00250, Finland.
42
Westat, Rockville, 20850, MD, USA.
43
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, 38105, TN, USA.
44
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20877, MD, USA.
45
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Baden-Württemberg, Germany.
46
Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, 08908, Spain.
47
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, 28029, Spain.
48
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, 65653, Czech Republic.
49
EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon, 21070, France.
50
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, 79108, Baden-Württemberg, Germany.
51
School of Nursing and Human Sciences, Dublin City University, Dublin, 9, Ireland.
52
Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
53
Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, 94720, CA, USA.
54
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 75105, Sweden.
55
Department of Hematology, Rigshospitalet, Copenhagen, 2100, Denmark.
56
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
57
Department of Epidemiology, Brown University, Providence, 02903, RI, USA.
58
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA.
59
Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA.
60
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98117, WA, USA.
61
Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA.
62
Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA.
63
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, 48201, MI, USA.
64
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, 06520, CT, USA.
65
Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, 43210, OH, USA.
66
Ontario Health Study, Toronto, M5S 1C6, ON, Canada.
67
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, 21205, MD, USA.
68
Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, 21205, MD, USA.
69
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, 30322, GA, USA.

Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

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