BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region. METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.

Centre of Chronic Immunodeficiency Freiburg University Medical Centre Freiburg Freiburg Germany

Clinical Epidemiology Unit Department of Medicine Karolinska Institutet Stockholm Sweden Department of Radiology Oncology and Clinical Immunology Uppsala University Uppsala Sweden

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

Department of Epidemiology Research Statens Serum Institut Copenhagen Denmark

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

Department of Medicine Solna Clinical Epidemiology Unit Karolinska Institute and Karolinska University Hospital Stockholm Sweden

Department of Pathology and Medical Biology University of Groningen University Medical Centre Groningen Groningen the Netherlands

Department of Public Health Occupational Health Section University of Cagliari Cagliari Italy

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Epidemiology and Genetics Unit Department of Health Sciences University of York York United Kingdom

International Agency for Research on Cancer Lyon France

McGill University and Genome Quebec Innovation Centre Montreal Quebec Canada

MRC University of Glasgow Centre for Virus Research University of Glasgow Glasgow United Kingdom

Norwegian University of Science and Technology Trondheim Norway

Radboud University Medical Centre Radboud Institute for Health Sciences Nijmegen the Netherlands

Registry of Hematological Malignancies University of Burgundy University Hospital of Dijon Dijon France

School of Nursing Dublin City University Glasnevin Dublin Ireland

Sorbonne Paris Cité Epidemiology and Biostatistics Research Center Inserm U1153 Inra U1125 Cnam University Paris 13 University Paris 5 University Paris 7 Bobigny France

Unit of Infections and Cancer Cancer Epidemiology Research Programme IDIBELL Catalan Institute of Oncology Barcelona Spain

Unit of Infections and Cancer Cancer Epidemiology Research Programme IDIBELL Catalan Institute of Oncology Barcelona Spain CIBER de Epidemiología y Salud Pública Madrid Spain

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