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.

Bill Lyons Informatics Centre UCL Cancer Institute University College London London WC1E 6DD UK

Cancer Biology and Genetics Program Memorial Sloan Kettering Cancer Center New York 10065 NY USA

Cancer Epidemiology Research Programme Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona 08908 Spain

Cancer Epidemiology Unit University of Oxford Oxford OX3 7LF UK

Cancer Genomics Research Laboratory Leidos Biomedical Research Inc Frederick National Lab for Cancer Research Frederick 20877 MD USA

Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill 27599 NC USA

Center for Chronic Immunodeficiency University Medical Center Freiburg Freiburg 79108 Baden Württemberg Germany

Centre for Big Data Research in Health University of New South Wales Sydney 2052 NSW Australia

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston 02115 MA USA

CIBER Epidemiología y Salud Pública Madrid 28029 Spain

Department of Biostatistics Bloomberg School of Public Health Johns Hopkins University Baltimore 21205 MD USA

Department of Biostatistics Harvard T H Chan School of Public Health Boston 02115 MA USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and MF MU Brno 65653 Czech Republic

Department of Community Medicine Faculty of Health Sciences University of Tromsø The Arctic University of Norway Tromsø 9019 Norway

Department of Computational Biology St Jude Children's Research Hospital Memphis 38105 TN USA

Department of Environmental Health Sciences Yale School of Public Health New Haven 06520 CT USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco 94118 CA USA

Department of Epidemiology Brown University Providence 02903 RI USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston 02115 MA USA

Department of Epidemiology School of Public Health and Comprehensive Cancer Center University of Alabama at Birmingham Birmingham 35233 AL USA

Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill 27599 NC USA

Department of Family Medicine and Public Health Sciences Wayne State University Detroit 48201 MI USA

Department of Health Sciences Research Mayo Clinic Rochester 55905 MN USA

Department of Health Sciences University of York York YO10 5DD UK

Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta 30322 GA USA

Department of Hematology Rigshospitalet Copenhagen 2100 Denmark

Department of Immunology Genetics and Pathology Uppsala University Uppsala 75105 Sweden

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City 52242 IA USA

Department of Internal Medicine Mayo Clinic Rochester 55905 MN USA

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester 55905 MN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm 17177 Sweden

Department of Medicine Memorial Sloan Kettering Cancer Center New York 10065 NY USA

Department of Medicine Solna Karolinska Institutet Stockholm 17176 Sweden

Department of Medicine Stanford University School of Medicine Stanford 94305 CA USA

Department of Nutrition Harvard T H Chan School of Public Health Boston 02115 MA USA

Department of Oncology School of Medicine Johns Hopkins University Baltimore 21205 MD USA

Department of Pathology University of Alabama at Birmingham Birmingham 35233 AL USA

Department of Preventive Medicine USC Keck School of Medicine University of Southern California Los Angeles 90033 CA USA

Department of Research Cancer Registry of Norway Institute of Population Based Cancer Research Oslo 0379 Norway

Department of Statistics Dongguk University Seoul 100 715 Republic of Korea

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda 20892 MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg 69120 Baden Württemberg Germany

Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus 43210 OH USA

Division of Environmental Health Sciences University of California Berkeley School of Public Health Berkeley 94720 CA USA

Division of Health Surveillance and Research Department of Epidemiology Research Statens Serum Institut Copenhagen 2300 Denmark

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle 98117 WA USA

EA 4184 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital Dijon 21070 France

Epidemiology of Childhood and Adolescent Cancers Group Inserm Center of Research in Epidemiology and Statistics Sorbonne Paris Cité Paris F 94807 France

Epidemiology Research Program American Cancer Society Atlanta 30303 GA USA

Genetic Epidemiology Group Folkhälsan Research Center and University of Helsinki Helsinki 00250 Finland

Genomic Epidemiology Group German Cancer Research Center Heidelberg 69120 Germany

Hematology Center Karolinska University Hospital Stockholm 17176 Sweden

Human Genetics Foundation Turin 10126 Italy

Institute for Risk Assessment Sciences Utrecht University Utrecht 3508 TD The Netherlands

Institute of Health and Society Clinical Effectiveness Research Group University of Oslo Oslo NO 0316 Norway

International Agency for Research on Cancer Lyon 69372 France

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht 3584 CX The Netherlands

Laboratory of Translational Genomics Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda 20877 MD USA

MRC PHE Centre for Environment and Health School of Public Health Imperial College London London W2 1PG UK

Norris Comprehensive Cancer Center USC Keck School of Medicine University of Southern California Los Angeles 90033 CA USA

Ontario Health Study Toronto M5S 1C6 ON Canada

Registry of Hematological Malignancies in Gironde Institut Bergonié University of Bordeaux Inserm Team EPICENE UMR 1219 Bordeaux 33000 France

School of Nursing and Human Sciences Dublin City University Dublin 9 Ireland

Service d'hématologie et Oncologie Centre Hospitalier de Versailles Le Chesnay Inserm U1018 Centre pour la Recherche en Epidémiologie et Santé des Populations Villejuif 78157 France

The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York 10029 NY USA

Tri Institutional Training Program in Computational Biology and Medicine Weill Cornell Graduate College New York 10021 NY USA

Université Paris Descartes Paris 75006 France

Westat Rockville 20850 MD USA

Zobrazit více v PubMed

Swerdlow, S. H. et al. in WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues 4th edn (eds Swerdlow, S. H. et al.) (International Agency for Research on Cancer, Lyon, 2008).

Teras LR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J. Clin. 2016;66:443–459. doi: 10.3322/caac.21357. PubMed DOI

Kristinsson SY, et al. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patients: a population-based study in Sweden. Blood. 2008;112:3052–3056. doi: 10.1182/blood-2008-06-162768. PubMed DOI PMC

Altieri A, Bermejo JL, Hemminki K. Familial aggregation of lymphoplasmacytic lymphoma with non-Hodgkin lymphoma and other neoplasms. Leukemia. 2005;19:2342–2343. doi: 10.1038/sj.leu.2403991. PubMed DOI

Koshiol J, Gridley G, Engels EA, McMaster ML, Landgren O. Chronic immune stimulation and subsequent Waldenström macroglobulinemia. Arch. Intern. Med. 2008;168:1903–1909. doi: 10.1001/archinternmed.2008.4. PubMed DOI PMC

Kristinsson SY, et al. Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. J. Natl Cancer Inst. 2010;102:557–567. doi: 10.1093/jnci/djq043. PubMed DOI PMC

Royer RH, et al. Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. Blood. 2010;115:4464–4471. doi: 10.1182/blood-2009-10-247973. PubMed DOI PMC

Vajdic CM, et al. Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J. Natl Cancer Inst. Monogr. 2014;2014:87–97. doi: 10.1093/jncimonographs/lgu002. PubMed DOI PMC

Treon SP, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N. Engl. J. Med. 2012;367:826–833. doi: 10.1056/NEJMoa1200710. PubMed DOI

McMaster ML, et al. Genomewide linkage screen for Waldenström macroglobulinemia susceptibility loci in high-risk families. Am. J. Hum. Genet. 2006;79:695–701. doi: 10.1086/507687. PubMed DOI PMC

Berndt SI, et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat. Genet. 2013;45:868–876. doi: 10.1038/ng.2652. PubMed DOI PMC

Berndt SI, et al. Two susceptibility loci identified for prostate cancer aggressiveness. Nat. Commun. 2015;6:6889. doi: 10.1038/ncomms7889. PubMed DOI PMC

Yang J, et al. Genomic inflation factors under polygenic inheritance. Eur. J. Hum. Genet. 2011;19:807–812. doi: 10.1038/ejhg.2011.39. PubMed DOI PMC

McCarthy S, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 2016;48:1279–1283. doi: 10.1038/ng.3643. PubMed DOI PMC

Helbig I, Hodge SE, Ottman R. Familial cosegregation of rare genetic variants with disease in complex disorders. Eur. J. Hum. Genet. 2013;21:444–450. doi: 10.1038/ejhg.2012.194. PubMed DOI PMC

Javierre BM, et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell. 2016;167:1369–1384. doi: 10.1016/j.cell.2016.09.037. PubMed DOI PMC

Mifsud B, et al. Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C. Nat. Genet. 2015;47:598–606. doi: 10.1038/ng.3286. PubMed DOI

Jin F, et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature. 2013;503:290–294. doi: 10.1038/nature12644. PubMed DOI PMC

Mayr C. Regulation by 3′-untranslated regions. Ann. Rev. Genet. 2017;51:171–194. doi: 10.1146/annurev-genet-120116-024704. PubMed DOI

Singh I, et al. Widespread intronic polyadenylation diversifies immune cell transcriptomes. Nat. Commun. 2018;9:1716. doi: 10.1038/s41467-018-04112-z. PubMed DOI PMC

Lianoglou S, Garg V, Yang JL, Leslie CS, Mayr C. Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev. 2013;27:2380–2396. doi: 10.1101/gad.229328.113. PubMed DOI PMC

Gruber AJ, et al. A comprehensive analysis of 3′ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation. Genome Res. 2016;26:1145–1159. doi: 10.1101/gr.202432.115. PubMed DOI PMC

Hofacker IL. Vienna RNA secondary structure server. Nucleic Acids Res. 2003;31:3429–3431. doi: 10.1093/nar/gkg599. PubMed DOI PMC

Cerami E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–404. doi: 10.1158/2159-8290.CD-12-0095. PubMed DOI PMC

Forbes SA, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–D783. doi: 10.1093/nar/gkw1121. PubMed DOI PMC

Lee DY, Deng Z, Wang CH, Yang BB. MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc. Natl Acad. Sci. USA. 2007;104:20350–20355. doi: 10.1073/pnas.0706901104. PubMed DOI PMC

Kuo WT, et al. MicroRNA-324 in human cancer: miR-324-5p and miR-324-3p have distinct biological functions in human cancer. Anticancer Res. 2016;36:5189–5196. doi: 10.21873/anticanres.11089. PubMed DOI

Dharap A, Pokrzywa C, Murali S, Pandi G, Vemuganti R. MicroRNA miR-324-3p induces promoter-mediated expression of RelA gene. PLoS ONE. 2013;8:e79467. doi: 10.1371/journal.pone.0079467. PubMed DOI PMC

Nagel D, Vincendiau M, Eitelhuber AC, Krappmann D. Mechanisms and consequences of constitutive NF-κB activation in B-cell lymphoid malignancies. Oncogene. 2014;33:5655–5665. doi: 10.1038/onc.2013.565. PubMed DOI

Yang G, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122:1222–1232. doi: 10.1182/blood-2012-12-475111. PubMed DOI

Cerhan JR, et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat. Genet. 2014;46:1233–1238. doi: 10.1038/ng.3105. PubMed DOI PMC

Bassig BA, et al. Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations. Eur. J. Haematol. 2015;95:442–448. doi: 10.1111/ejh.12513. PubMed DOI

De Silva NS, Simonetti G, Heise N, Klein U. The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol. Rev. 2012;247:73–92. doi: 10.1111/j.1600-065X.2012.01113.x. PubMed DOI

Feldman AL, et al. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively-parallel genomic sequencing. Blood. 2011;117:915–919. doi: 10.1182/blood-2010-08-303305. PubMed DOI PMC

Shukla V, Ma S, Hardy RR, Joshi SS, Lu R. A role for IRF4 in the development of CLL. Blood. 2013;122:2848–2855. doi: 10.1182/blood-2013-03-492769. PubMed DOI PMC

Gutiérrez NC, et al. Gene expression profiling of B lymphocytes and plasma cells from Waldenström’s macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals. Leukemia. 2007;21:541–549. doi: 10.1038/sj.leu.2404520. PubMed DOI

Roberts MJ, et al. Nuclear protein dysregulation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Hematopathol. 2013;139:210–219. PubMed

Ochiai K, et al. Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. Immunity. 2013;38:918–929. doi: 10.1016/j.immuni.2013.04.009. PubMed DOI PMC

Negishi H, et al. Negative regulation of Toll-like-receptor signaling by IRF4. Proc. Natl Acad. Sci. USA. 2005;102:15989–15994. doi: 10.1073/pnas.0508327102. PubMed DOI PMC

Lang R, Hammer M, Mages J. DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response. J. Immunol. 2006;177:7497–7504. doi: 10.4049/jimmunol.177.11.7497. PubMed DOI

Sekine Y, et al. Regulation of STAT3-mediated signaling by LMW-DSP2. Oncogene. 2006;25:5801–5806. doi: 10.1038/sj.onc.1209578. PubMed DOI

Fulciniti M, et al. MYD88-independent growth and survival effects of Sp1 transactivation in Waldenström macroglobulinemia. Blood. 2014;123:2673–2681. doi: 10.1182/blood-2014-01-550509. PubMed DOI PMC

Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461:788–793. doi: 10.1038/nature08476. PubMed DOI PMC

Kashatus DF. Ral GTPases in tumorigenesis: emerging from the shadows. Exp. Cell Res. 2013;319:2337–2342. doi: 10.1016/j.yexcr.2013.06.020. PubMed DOI PMC

Bodemann BO, White MA. Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat. Rev. Cancer. 2008;8:133–140. doi: 10.1038/nrc2296. PubMed DOI

Chien Y, et al. RalB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell. 2006;127:157–170. doi: 10.1016/j.cell.2006.08.034. PubMed DOI

Adams BD, Anastasiadou E, Esteller M, He L, Slack FJ. The inescapable influence of noncoding RNAs in cancer. Cancer Res. 2015;75:5206–5210. doi: 10.1158/0008-5472.CAN-15-1989. PubMed DOI PMC

Rapicavoli NA, et al. A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. eLife. 2013;2:e00762. doi: 10.7554/eLife.00762. PubMed DOI PMC

Huang W, et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature. 2015;528:517–522. doi: 10.1038/nature16193. PubMed DOI PMC

Carpenter S, et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science. 2013;341:789–792. doi: 10.1126/science.1240925. PubMed DOI PMC

Lemal R, et al. TCL1 expression patterns in Waldenström macroglobulinemia. Mod. Pathol. 2016;29:83–88. doi: 10.1038/modpathol.2015.122. PubMed DOI

Hoyer KK, et al. Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma. Proc. Natl Acad. Sci. USA. 2002;99:14392–14397. doi: 10.1073/pnas.212410199. PubMed DOI PMC

Laine J, Künstle G, Obata T, Sha M, Noguchi M. The protooncogene TCL1 is an Akt kinase coactivator. Mol. Cell. 2000;6:395–407. doi: 10.1016/S1097-2765(00)00039-3. PubMed DOI

Ropars V, et al. The TCL1A oncoprotein interacts directly with the NF-κB inhibitor IκB. PLoS ONE. 2009;4:e6567. doi: 10.1371/journal.pone.0006567. PubMed DOI PMC

Gaudio E, et al. Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies. Blood. 2012;119:180–187. doi: 10.1182/blood-2011-08-374561. PubMed DOI PMC

Zhou W, et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat. Genet. 2016;48:563–568. doi: 10.1038/ng.3545. PubMed DOI PMC

Turner JJ, et al. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood. 2010;116:e90–e98. doi: 10.1182/blood-2010-06-289561. PubMed DOI PMC

Yu K, et al. Population substructure and control selection in genome-wide association studies. PLoS ONE. 2008;3:e2551. doi: 10.1371/journal.pone.0002551. PubMed DOI PMC

Pritchard JK, Stephens M, Donnelly P. Inference of population structure using multilocus genotype data. Genetics. 2000;155:945–959. PubMed PMC

International HapMap Consortium et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449:851–861. doi: 10.1038/nature06258. PubMed DOI PMC

Price AL, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 2006;38:904–909. doi: 10.1038/ng1847. PubMed DOI

Vijai J, et al. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. PLoS Genet. 2013;9:e1003220. doi: 10.1371/journal.pgen.1003220. PubMed DOI PMC

Park JH, et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat. Genet. 2010;42:570–575. doi: 10.1038/ng.610. PubMed DOI PMC

Pharoah PD, et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat. Genet. 2002;31:33–36. doi: 10.1038/ng853. PubMed DOI

Yang J, et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 2010;42:565–569. doi: 10.1038/ng.608. PubMed DOI PMC

Lee SH, Wray NR, Goddard ME, Visscher PM. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 2011;88:294–305. doi: 10.1016/j.ajhg.2011.02.002. PubMed DOI PMC

Zhang Y, et al. Model-based analysis of ChIP-Seq (MACS) Genome Biol. 2008;9:R137. doi: 10.1186/gb-2008-9-9-r137. PubMed DOI PMC

Kasowski M, et al. Extensive variation in chromatin states across humans. Science. 2013;342:750–752. doi: 10.1126/science.1242510. PubMed DOI PMC

Falahati R, et al. Chemoselection of allogeneic HSC after murine neonatal transplantation without myeloablation or post-transplant immunosuppression. Mol. Ther. 2012;20:2180–2189. doi: 10.1038/mt.2012.136. PubMed DOI PMC

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Genome-wide meta-analysis of monoclonal gammopathy of undetermined significance (MGUS) identifies risk loci impacting IRF-6