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 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 and Neil E. Caporaso
Additional contact information
Mary L. McMaster: National Cancer Institute
Sonja I. Berndt: National Cancer Institute
Jianqing Zhang: University of Alabama at Birmingham
Susan L. Slager: Mayo Clinic
Shengchao Alfred Li: Frederick National Lab for Cancer Research
Claire M. Vajdic: University of New South Wales
Karin E. Smedby: Solna Karolinska Institutet
Huihuang Yan: Mayo Clinic
Brenda M. Birmann: Brigham and Women’s Hospital and Harvard Medical School
Elizabeth E. Brown: University of Alabama at Birmingham
Alex Smith: University of York
Geffen Kleinstern: Mayo Clinic
Mervin M. Fansler: Weill Cornell Graduate College
Christine Mayr: Memorial Sloan Kettering Cancer Center
Bin Zhu: Frederick National Lab for Cancer Research
Charles C. Chung: Frederick National Lab for Cancer Research
Ju-Hyun Park: Dongguk University
Laurie Burdette: Frederick National Lab for Cancer Research
Belynda D. Hicks: Frederick National Lab for Cancer Research
Amy Hutchinson: Frederick National Lab for Cancer Research
Lauren R. Teras: American Cancer Society
Hans-Olov Adami: Karolinska Institutet
Paige M. Bracci: University of California, San Francisco
James McKay: International Agency for Research on Cancer (IARC)
Alain Monnereau: Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS)
Brian K. Link: The University of Iowa
Roel C. H. Vermeulen: Utrecht University
Stephen M. Ansell: Mayo Clinic
Ann Maria: Memorial Sloan Kettering Cancer Center
W. Ryan Diver: American Cancer Society
Mads Melbye: Statens Serum Institut
Akinyemi I. Ojesina: University of Alabama at Birmingham
Peter Kraft: Harvard T.H. Chan School of Public Health
Paolo Boffetta: Icahn School of Medicine at Mount Sinai
Jacqueline Clavel: Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS)
Edward Giovannucci: Brigham and Women’s Hospital and Harvard Medical School
Caroline M. Besson: Centre pour la Recherche en Epidémiologie et Santé des Populations (CESP)
Federico Canzian: German Cancer Research Center (DKFZ)
Ruth C. Travis: University of Oxford
Paolo Vineis: Imperial College London
Elisabete Weiderpass: Karolinska Institutet
Rebecca Montalvan: Westat
Zhaoming Wang: St. Jude Children’s Research Hospital
Meredith Yeager: Frederick National Lab for Cancer Research
Nikolaus Becker: German Cancer Research Center (DKFZ)
Yolanda Benavente: L’Hospitalet de Llobregat
Paul Brennan: International Agency for Research on Cancer (IARC)
Lenka Foretova: Masaryk Memorial Cancer Institute and MF MU
Marc Maynadie: University of Burgundy and Dijon University Hospital
Alexandra Nieters: University Medical Center Freiburg
Silvia Sanjose: L’Hospitalet de Llobregat
Anthony Staines: Dublin City University
Lucia Conde: University College London
Jacques Riby: University of Alabama at Birmingham
Bengt Glimelius: Uppsala University
Henrik Hjalgrim: Statens Serum Institut
Nisha Pradhan: Memorial Sloan Kettering Cancer Center
Andrew L. Feldman: Mayo Clinic
Anne J. Novak: Mayo Clinic
Charles Lawrence: Westat
Bryan A. Bassig: National Cancer Institute
Qing Lan: National Cancer Institute
Tongzhang Zheng: Brown University
Kari E. North: University of North Carolina at Chapel Hill
Lesley F. Tinker: Fred Hutchinson Cancer Research Center
Wendy Cozen: University of Southern California
Richard K. Severson: Wayne State University
Jonathan N. Hofmann: National Cancer Institute
Yawei Zhang: Yale School of Public Health
Rebecca D. Jackson: The Ohio State University
Lindsay M. Morton: National Cancer Institute
Mark P. Purdue: National Cancer Institute
Nilanjan Chatterjee: National Cancer Institute
Kenneth Offit: Memorial Sloan Kettering Cancer Center
James R. Cerhan: Mayo Clinic
Stephen J. Chanock: National Cancer Institute
Nathaniel Rothman: National Cancer Institute
Joseph Vijai: Memorial Sloan Kettering Cancer Center
Lynn R. Goldin: National Cancer Institute
Christine F. Skibola: Emory University School of Medicine
Neil E. Caporaso: National Cancer Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06541-2

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