Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Open Access

Abstract

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response. ; In the United Kingdom, Bloodwise (LLR; 10021) provided principal funding for the study. Support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Lymphoma Research Trust is also acknowledged. A.S. is supported by a clinical fellowship from Cancer Research UK. For the UK-GWAS, sample and data acquisition were supported by Breast Cancer Now, the European Union and the Lymphoma Research Trust. The UK-GWAS made use of control genotyping data generated by the WTCCC. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, which was funded by the Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for this project was provided by the Wellcome Trust under awards 076113 and 085475. Patients for the new GWAS were ascertained through the National Study of Hodgkin Lymphoma Genetics (http://www.public.ukcrn.org.uk) and we thank the HighThroughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of Genotyping data. The BCAC study would not have been possible without the contributions of the following: Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou and Joe Dennis. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A16563). For the BBCS study, we thank Eileen Williams, Elaine Ryder-Mills, Kara Sargus. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) and the National Cancer Research Network (NCRN). We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/ A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). We thank the SEARCH and EPIC teams, which were funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK NIHR BRC at the University of Cambridge. We thank Breast Cancer Now and the Institute of Cancer Research (ICR) for support and funding of the UKBGS, and the study participants, study staff, and the doctors, nurses and other health-care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR BRC. UKGPCS would like to thank The Institute of Cancer Research and The Everyman Campaign for funding support. The UKGPCS acknowledges The Prostate Cancer Research Foundation, Prostate Action, The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI), the NIHR funding to the NIHR Biomedical Research data managers and consultants for their work in the UKGPCS study and urologists and other persons involved in the planning, and data collection of the CAPS study. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I). Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/ A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175), and The National Institute of Health (NIH) Cancer PostCancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The APBC BioResource, which form part of the PRACTICAL consortium, consists of the following members: Wayne Tilley, Gail Risbridger, Renea Taylor, Judith A Clements, Lisa Horvath, Vanessa Hayes, Lisa Butler, Trina Yeadon, Allison Eckert, Pamela Saunders, Anne-Maree Haynes, Melissa Papargiris. At the MRC University of Glasgow Centre for Virus Research, funding was provided by Leukaemia Lymphoma Research (12022). The Scotland and Newcastle Epidemiological Study of Hodgkin Disease (SNEHD) was funded by the Kay Kendall Leukaemia Fund and the Young Adult Hodgkin Case–Control Study (YHCCS) and the Epidemiology and Cancer Statistics Group Lymphoma Case–Control Study (ELCCS) were funded by Bloodwise. German funding was provided by the German Cancer Aid, the Harald Huppert Foundations, The German Federal Ministry of Education and Research (eMed, Cliommics 01ZX1309B), the Multiple Myeloma Research Foundation, the Heinz Nixdorf Foundation (Germany), the Ministerium für Innovation, Wissenschaft und Forschung des Landes NordrheinWestfalen and the Faculty of Medicine University Duisburg–Essen. For their help with UK sample collection we thank Hayley Evans, James Griffin, Joanne Micic, Susan Blackmore, Beverley Smith, Deborah Hogben, Alison Butlin, Jill Wood, Margot Pelerin, Alison Hart, Katarzyna Tomczyk and Sarah Chilcott-Burns