Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

] [2]

] International Agency for Research on Cancer 69372 Lyon France [2]

] International Agency for Research on Cancer 69372 Lyon France [2] Institute of Genetics and Molecular Medicine University of Edinburgh EH4 2XU Edinburgh UK [3]

] Karolinska Institutet and Karolinska University Hospital S 221 00 Stockholm Sweden [2] Harvard University School of Public Health Boston Massachusetts 02115 USA

] MRC University of Glasgow Centre for Virus Research Garscube Estate University of Glasgow G12 8QQ Glasgow Scotland UK [2]

] Statens Serum Institut DK 2300 Copenhagen Denmark [2]

] The University of Chicago Chicago Illinois 60637 5415 USA [2]

] University of Groningen University Medical Centre Groningen 9700 RB Groningen The Netherlands [2]

] USC Keck School of Medicine Norris Comprehensive Cancer Center University of Southern California Los Angeles California 90089 9175 USA [2]

Cancer Prevention Institute of California Fremont California 94538 USA

Centre Léon Bérard UMR CNRS 5239 Université Lyon 1 69008 Lyon France

CHU de Dijon EA 4184 University of Burgundy 21070 Dijon France

City of Hope National Medical Center Duarte California 91010 USA

Clarient Pathology Services Aliso Viejo California 92656 USA

Department of Human Genetics and Disease Diversity Tokyo Medical and Dental University Tokyo 104 0044 Japan

Genome Quebec Montreal Canada H3A 0G1

German Cancer Research Centre D 69120 Heidelberg Germany

Icahn School of Medicine at Mount Sinai New York City New York 10029 6574 USA

IDIBELL Institut Català d'Oncologia 8907 Barcelona Spain

INSERM U557 93017 Paris France

Institute of Occupational Health University of Cagliari Monserrato 09042 Cagliari Italy

International Agency for Research on Cancer 69372 Lyon France

Karolinska Institutet and Karolinska University Hospital S 221 00 Stockholm Sweden

Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

Mayo Clinic Rochester Minnesota 55905 USA

MD Anderson Cancer Center University of Texas Houston Texas 77030 USA

MRC University of Glasgow Centre for Virus Research Garscube Estate University of Glasgow G12 8QQ Glasgow Scotland UK

Norwegian University of Science and Technology NO 7491 Trondheim Norway

Radboud University Nijmegen Medical Centre 6500HB Nijmegen The Netherlands

School of Cancer Sciences University of Manchester St Mary's Hospital M13 0JH Manchester UK

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

St Jude Children's Hospital Cordova Tennessee 38105 USA

Statens Serum Institut DK 2300 Copenhagen Denmark

The University of Chicago Chicago Illinois 60637 5415 USA

University Medical Centre Freiburg D 79085 Freiburg Germany

University of Groningen University Medical Centre Groningen 9700 RB Groningen The Netherlands

University of Iowa College of Medicine Iowa City Iowa 52242 USA

University of York YO10 5DD York UK

Uppsala University 75285 Uppsala Sweden

USC Keck School of Medicine Norris Comprehensive Cancer Center University of Southern California Los Angeles California 90089 9175 USA

Zobrazit více v PubMed

Mani H, Jaffe E. Hodgkin lymphoma: an update on its biology with newer insights into classification. Clin Lymph Myeloma. 2009;9:206–216. PubMed PMC

Mueller N, Grufferman S. In: Cancer Epidemiology and Prevention. Schottenfeld D, Fraumeni JF Jr, editors. Oxford University Press; 2006. pp. 872–898.

Curado MP, Edwards B, Shin HR, Ferlay J, Heanue M, Boyle P, Storm H, editors. Cancer Incidence in Five Continents, Volume IX, IARC Scientific Publication, No 160. IX. WHO Press; 2008.

Cozen W, Katz J, Mack T. Hodgkin’s disease varies by cell type in Los Angeles. Cancer Epidemiol Biomarkers Preven. 1992;1:261–268. PubMed

Glaser S, et al. Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations. Int J Cancer. 2008;123:1499–1507. PubMed PMC

Hjalgrim H. On the aetiology of Hodgkin lymphoma. Dan Med J. 2012;59 PubMed

Mack T, et al. Concordance for Hodgkin’s disease in identical twins suggests genetic susceptibility to the young-adult form of the disease. N Eng J Med. 1995;332:413–418. PubMed

Grufferman S, Cole P, Smith P, Lukes R. Hodgkin’s disease in siblings. N Eng J Med. 1977;296:248–250. PubMed

Niens M, et al. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood. 2007;110:3310–3315. PubMed

Huang X, et al. HLA associations in classical Hodgkin lymphoma: EBV status matters. PLos One. 2012;7:e0039986. PubMed PMC

Enciso-Mora V, et al. A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p15.1 (REL), 8q24.21 and 10p14 (GATA3) Nat Genet. 2010;42:1126–1230. PubMed PMC

Urayama K, et al. Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Nat Cancer Inst. 2012;104:1–14. PubMed PMC

Cozen W, et al. A Meta-Analysis of nodular sclerosis Hodgkin lymphoma identifies risk loci at 6p21.32. Blood. 2012;119:469–475. PubMed PMC

Best T, et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin lymphoma. Nat Med. 2010;17:941–943. PubMed PMC

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis G. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44:955–959. PubMed PMC

Freedman M, et al. Assessing the impact of population stratification on genetic association studies. Nat Genet. 2004;36:388–393. PubMed

Frampton M, et al. Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin lymphoma. Nat Comm. 2013;4:e2549. PubMed PMC

Coetzee S, Rhie S, Berman B, Coetzee G, Noushmehr H. FunciSNP: an R/bioconductor tool integrating functional non-coding data sets with genetic association studies to identify candidate regulatory SNPs. Nucleic Acids Res. 2012;40:e139. PubMed PMC

1000 Genomes Project Consortium et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. PubMed PMC

Khatun J, et al. Whole human genome proteogenomic mapping for ENCODE cell line data: identifying protein-coding regions. BMC Genomics. 2013;14:141. doi: 10.1186/1471-2164-14-141. PubMed DOI PMC

Yang T, et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics. 2010;26:2474–2476. PubMed PMC

Schmitz R, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490:116–120. PubMed PMC

Fairfax B, et al. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet. 2012;445:502–510. PubMed PMC

Kwon K, et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity. 2008;28:751–762. PubMed

Lazorchak A, Wojciechowski J, Dai M, Zhuang Y. E2A promotes the survival of precursor and mature B lymphocytes. J Immunol. 2006;177:2495–2504. PubMed PMC

Renné C, M-SJ, Eickernjäger M, Hansmann ML, Küppers R, Siebert R, Bräuninger A. Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin’s lymphoma. Am J Pathol. 2006;169:655–664. PubMed PMC

Mathas S, et al. Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol. 2006;7:207–215. PubMed

Van der Put E, Frasca D, King A, Blomberg B, Riley R. Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. J Immunol. 2004;173:818–827. PubMed

Besson H, et al. Tobacco smoking, alcohol drinking and Hodgkin’s lymphoma: a European multi-centre case-control study (EPILYMPH) Br J Cancer. 2006;95:378–384. PubMed PMC

Jarrett R, et al. The Scotland and Newcastle epidemiological study of Hodgkin’s disease: impact of histopathological review and EBV status on incidence estimates. J Clin Pathol. 2003;56:811–816. PubMed PMC

Smedby K, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst. 2005;97:199–209. PubMed

Hjalgrim H, et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2010;107:6400–6405. PubMed PMC

Diepstra A, et al. Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin’s lymphoma. Lancet. 2005;365:2216–2224. PubMed

Lagiou P, et al. Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection. Eur J Cancer Prev. 2009;18:76–84. PubMed

Hashibe M, et al. Multiple ADH genes are associated with upper aerodigestive cancers. Nat Genet. 2008;40:707–709. PubMed

Amundadottir L, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41:986–990. PubMed PMC

Wetzels J, Kiemeney L, Swinkels D, Willems H, den Heijer M. Age- and gender-specific reference values of estimated GFR in Caucasians: the Nijmegen Biomedical Study. Kidney Int. 2007;72:632–637. PubMed

Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678. PubMed PMC

Cozen W, et al. The USC Adult Twin Cohorts: International Twin Study and California Twin Program. Twin Res Hum Genet. 2013;16:366–370. PubMed

Weiss L, Chen Y, Liu X, Shibata D. Epstein-Barr virus and Hodgkin’s disease. A correlative in situ hybridization and polymerase chain reaction study. Am J Pathol. 1991;139:1259–1265. PubMed PMC

Mailman M, et al. The NCBI dbGaP database of genotypes and phenotypes. Nat Genet. 2007;39:1181–1186. PubMed PMC

Hunter D, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39:870–874. PubMed PMC

Robison L, et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J Clin Oncol. 2009;27:2308–2318. PubMed PMC

GAIN Collaborative Research Group, et al. New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet. 2007;39:1045–1051. PubMed

Howie B, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5:e1000529. PubMed PMC

Li Y, Willer C, Ding J, Scheet P, Abecasis G. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol. 2010;34:816–834. PubMed PMC

Casasnovas R, et al. Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin’s lymphoma: a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2007;25:1732–1740. PubMed

Willett EV, OCS, Smith AG, Roman E. Does smoking or alcohol modify the risk of Epstein-Barr virus- positive or negative Hodgkin lymphoma? Epidemiology. 2007;18:130–136. PubMed

Cerhan J, et al. Design and validity of a clinic-based case-control study on the molecular epidemiology of lymphoma. Int J Mol Epidemiol Genet. 2011;2:95–113. PubMed PMC

Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. PubMed PMC

Pruim R, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–2337. PubMed PMC

Johnson A, et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008;24:2938–2939. PubMed PMC

Price A, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909. PubMed

Stram DO. In: Design, Analysis, and Interpretation of Genome-Wide Association Scans. Gail M, Krickenberg K, Samet J, Tsiatis A, Wong W, editors. Springer; 2014.

Kent W, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006. PubMed PMC

Wang J, et al. Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res. 2012;22:1798–1812. PubMed PMC

Poppema S, De Jong B, Atmosoerodjo J, Idenburg V, Visser L, De Ley L. Morphologic, immunologic, enzyme histochemical and chromosomal analysis of a cell line derived from Hodgkin’s disease. Evidence for a B-cell origin of Sternberg-Reed cells. Cancer. 1985;55:683–690. PubMed

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Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis