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

  • Mary L McMaster
  • , Sonja I Berndt
  • , Jianqing Zhang
  • , Susan L Slager
  • , Shengchao Alfred Li
  • , Claire M Vajdic
  • , Karin E Smedby
  • , Huihuang Yan
  • , Brenda M Birmann
  • , Elizabeth E Brown
  • , Alex Smith
  • , Geffen Kleinstern
  • , Mervin M Fansler
  • , Christine Mayr
  • , Bin Zhu
  • , Charles C Chung
  • , Ju-Hyun Park
  • , Laurie Burdette
  • , Belynda D Hicks
  • , Amy Hutchinson
    • Lauren R Teras, Hans-Olov Adami, Paige M Bracci, James McKay, Alain Monnereau, Brian K Link, Roel C H Vermeulen, Stephen M Ansell, Ann Maria, W Ryan Diver, Mads Melbye, Akinyemi I Ojesina, Peter Kraft, Paolo Boffetta, Jacqueline Clavel, Edward Giovannucci, Caroline M Besson, Federico Canzian, Ruth C Travis, Paolo Vineis, Elisabete Weiderpass, Rebecca Montalvan, Zhaoming Wang, Meredith Yeager, Nikolaus Becker, Yolanda Benavente, Paul Brennan, Lenka Foretova, Marc Maynadie, Alexandra Nieters, Silvia de Sanjose, Anthony Staines, Lucia Conde, Jacques Riby, Bengt Glimelius, Henrik Hjalgrim, Nisha Pradhan, Andrew L Feldman, Anne J Novak, Charles Lawrence, Bryan A Bassig, Qing Lan, Tongzhang Zheng, Kari E North, Lesley F Tinker, Wendy Cozen, Richard K Severson, Jonathan N Hofmann, Yawei Zhang, Rebecca D Jackson, Lindsay M Morton, Mark P Purdue, Nilanjan Chatterjee, Kenneth Offit, James R Cerhan, Stephen J Chanock, Nathaniel Rothman, Joseph Vijai, Lynn R Goldin, Christine F Skibola, Neil E Caporaso
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, MD, USA. [email protected].
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, MSC 9778, Bethesda, MD 20892, 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.
  • Hematology Center, Karolinska University Hospital, 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.
  • 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.
  • Institute of Health and Society, Clinical Effectiveness Research Group, University of Oslo, Oslo, NO-0316, Norway.
  • Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, 94118, CA, USA.
  • International Agency for Research on Cancer (IARC), Section of Environment and Radiation, 69372 Lyon, France.
  • Registry of Hematological Malignancies in Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, Bordeaux, 33000, France.
  • Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, 52242, IA, USA.
  • Institute for Risk Assessment Sciences
  • Institute for Risk Assessment Sciences, Utrecht University, Yalelaan 2, 3584 CM Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 80178, 3508 TD Utrecht, The Netherlands. Electronic address: [email protected].
  • Department of Internal Medicine, Mayo Clinic, Rochester, 55905, MN, USA.
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
  • Department of Medicine, Stanford University School of Medicine, Stanford, 94305, CA, USA.
  • Department of Biostatistics, 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.
  • Université Paris Descartes, Paris, 75006, France.
  • Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, 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.
  • Human Genetics Foundation, Turin, 10126, Italy.
  • Genetic Epidemiology Group, Folkhälsan Research Center and University of Helsinki, Helsinki, 00250, Finland.
  • Westat, Rockville, 20850, MD, USA.
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20877, MD, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Baden-Württemberg, Germany.
  • CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, 28029, 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.
  • Dublin City University
  • Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
  • Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, 94720, CA, USA.
  • Uppsala University
  • Department of Hematology, Rigshospitalet, Copenhagen, 2100, Denmark.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA.
  • Department of Epidemiology, Brown University, Providence, 02903, RI, USA.
  • University of North Carolina at Chapel Hill
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98117, WA, USA.
  • Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA.
  • Wayne State University
  • Department of Environmental Health Sciences, Yale School of Public Health, New Haven, 06520, CT, USA.
  • Ohio State University
  • Ontario Health Study, Toronto, M5S 1C6, ON, Canada.
  • Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, 21205, MD, USA.
  • Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, 30322, GA, USA.

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original languageEnglish
Article number4182
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Oct 2018

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