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

About this Publication
Title
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.
Pubmed ID
30305637 (View this publication on the PubMed website)
Publication
Nat Commun. 2018 Oct; Volume 9 (Issue 1): Pages 4182
Authors
McMaster ML, Berndt SI, Zhang J, Slager SL, Li SA, Vajdic CM, Smedby KE, Yan H, Birmann BM, Brown EE, Smith A, Kleinstern G, Fansler MM, Mayr C, Zhu B, Chung CC, Park JH, Burdette L, Hicks BD, Hutchinson A, ...show more Teras LR, Adami HO, Bracci PM, McKay J, Monnereau A, Link BK, Vermeulen RCH, Ansell SM, Maria A, Diver WR, Melbye M, Ojesina AI, Kraft P, Boffetta P, Clavel J, Giovannucci E, Besson CM, Canzian F, Travis RC, Vineis P, Weiderpass E, Montalvan R, Wang Z, Yeager M, Becker N, Benavente Y, Brennan P, Foretova L, Maynadie M, Nieters A, de Sanjose S, Staines A, Conde L, Riby J, Glimelius B, Hjalgrim H, Pradhan N, Feldman AL, Novak AJ, Lawrence C, Bassig BA, Lan Q, Zheng T, North KE, Tinker LF, Cozen W, Severson RK, Hofmann JN, Zhang Y, Jackson RD, Morton LM, Purdue MP, Chatterjee N, Offit K, Cerhan JR, Chanock SJ, Rothman N, Vijai J, Goldin LR, Skibola CF, Caporaso NE
Affiliations
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA. Mary.McMaster@nih.hhs.gov.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA.
  • Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, 35233, AL, USA.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, 55905, MN, USA.
  • Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick National Lab for Cancer Research, Frederick, 20877, MD, USA.
  • Centre for Big Data Research in Health, University of New South Wales, Sydney, 2052, NSW, Australia.
  • Department of Medicine, Solna Karolinska Institutet, Stockholm, 17176, Sweden.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
  • Department of Pathology, University of Alabama at Birmingham, Birmingham, 35233, AL, USA.
  • Department of Health Sciences, University of York, York, YO10 5DD, UK.
...show more
  • Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Graduate College, New York, 10021, NY, USA.
  • Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
  • Department of Statistics, Dongguk University, Seoul, 100-715, Republic of Korea.
  • Epidemiology Research Program, American Cancer Society, Atlanta, 30303, GA, USA.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
  • Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, 94118, CA, USA.
  • International Agency for Research on Cancer (IARC), Lyon, 69372, France.
  • Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, F-94807, France.
  • Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, 52242, IA, USA.
  • Institute for Risk Assessment Sciences, Utrecht University, Utrecht, 3508 TD, The Netherlands.
  • Department of Internal Medicine, Mayo Clinic, Rochester, 55905, MN, USA.
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
  • Division of Health Surveillance and Research, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2300, Denmark.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA.
  • The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
  • 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.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
  • Cancer Epidemiology Unit, University of Oxford, Oxford, OX3 7LF, UK.
  • MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK.
  • Westat, Rockville, 20850, MD, USA.
  • Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, 38105, TN, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Baden-Württemberg, Germany.
  • Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, 08908, Spain.
  • Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, 65653, Czech Republic.
  • EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon, 21070, France.
  • Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, 79108, Baden-Württemberg, Germany.
  • School of Nursing and Human Sciences, Dublin City University, Dublin, 9, Ireland.
  • Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
  • Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 75105, Sweden.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
  • Department of Epidemiology, Brown University, Providence, 02903, RI, USA.
  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98117, WA, USA.
  • Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA.
  • Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, 48201, MI, USA.
  • Department of Environmental Health Sciences, Yale School of Public Health, New Haven, 06520, CT, USA.
  • Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, 43210, OH, USA.
  • 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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