A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3) (original) (raw)
References
- Kuppers, R. The biology of Hodgkin's lymphoma. Nat. Rev. Cancer 9, 15–27 (2009).
Article Google Scholar - Swerdlow, A.J. Epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma. Eur. J. Nucl. Med. Mol. Imaging 30 Suppl 1, S3–S12 (2003).
Article Google Scholar - Smith, A. et al. The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research. Br. J. Haematol. 148, 739–753 (2010).
Article Google Scholar - Kutok, J.L. & Wang, F. Spectrum of Epstein-Barr virus–associated diseases. Annu. Rev. Pathol. 1, 375–404 (2006).
Article CAS Google Scholar - Goldin, L.R. et al. Familial aggregation of Hodgkin lymphoma and related tumors. Cancer 100, 1902–1908 (2004).
Article Google Scholar - Amiel, J. Study of the leukocyte phenotypes in Hodgkin's disease. in Histocompatibility Testing (ed, Teraski, P.I.) (Munksgaard, Copenhagen, Denmark, 1967).
- Klitz, W., Aldrich, C.L., Fildes, N., Horning, S.J. & Begovich, A.B. Localization of predisposition to Hodgkin disease in the HLA class II region. Am. J. Hum. Genet. 54, 497–505 (1994).
CAS PubMed PubMed Central Google Scholar - Oza, A.M. et al. A clinical and epidemiological study of human leukocyte antigen-DPB alleles in Hodgkin's disease. Cancer Res. 54, 5101–5105 (1994).
CAS PubMed Google Scholar - 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. USA 107, 6400–6405 (2010).
Article CAS Google Scholar - 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 110, 3310–3315 (2007).
Article CAS Google Scholar - Risch, N. Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. Hum. Genet. 40, 1–14 (1987).
CAS PubMed PubMed Central Google Scholar - Goldin, L.R. et al. A genome screen of families at high risk for Hodgkin lymphoma: evidence for a susceptibility gene on chromosome 4. J. Med. Genet. 42, 595–601 (2005).
Article CAS Google Scholar - Mack, T.M. et al. Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N. Engl. J. Med. 332, 413–418 (1995).
Article CAS Google Scholar - Power, C. & Elliott, J. Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006).
Article Google Scholar - Clayton, D.G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).
Article CAS Google Scholar - Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Article CAS Google Scholar - Wellcome Trust Case-Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
- Cabannes, E., Khan, G., Aillet, F., Jarrett, R.F. & Hay, R.T. Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 18, 3063–3070 (1999).
Article CAS Google Scholar - Emmerich, F. et al. Overexpression of IκBα without inhibition of NF-κB activity and mutations in the IκBα gene in Reed-Sternberg cells. Blood 94, 3129–3134 (1999).
CAS PubMed Google Scholar - Schmitz, R. et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J. Exp. Med. 206, 981–989 (2009).
Article CAS Google Scholar - Barth, T.F. et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 101, 3681–3686 (2003).
Article CAS Google Scholar - Joos, S. et al. Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int. J. Cancer 103, 489–495 (2003).
Article CAS Google Scholar - Martin-Subero, J.I. et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 99, 1474–1477 (2002).
Article CAS Google Scholar - Villeneuve, L., Rassart, E., Jolicoeur, P., Graham, M. & Adams, J.M. Proviral integration site Mis-1 in rat thymomas corresponds to the pvt-1 translocation breakpoint in murine plasmacytomas. Mol. Cell. Biol. 6, 1834–1837 (1986).
Article CAS Google Scholar - Beck-Engeser, G.B. et al. Pvt1-encoded microRNAs in oncogenesis. Retrovirology 5, 4 (2008).
Article Google Scholar - Bakkus, M.H., Brakel-van Peer, K.M., Michiels, J.J., van 't Veer, M.B. & Benner, R. Amplification of the c-myc and the pvt-like region in human multiple myeloma. Oncogene 5, 1359–1364 (1990).
CAS PubMed Google Scholar - Huppi, K., Siwarski, D., Skurla, R., Klinman, D. & Mushinski, J.F. Pvt-1 transcripts are found in normal tissues and are altered by reciprocal(6;15) translocations in mouse plasmacytomas. Proc. Natl. Acad. Sci. USA 87, 6964–6968 (1990).
Article CAS Google Scholar - Storlazzi, C.T. et al. Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies. Hum. Mol. Genet. 13, 1479–1485 (2004).
Article CAS Google Scholar - Crowther-Swanepoel, D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).
Article CAS Google Scholar - Gudmundsson, J. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39, 631–637 (2007).
Article CAS Google Scholar - Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).
Article CAS Google Scholar - Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).
Article CAS Google Scholar - Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).
Article CAS Google Scholar - Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
Article CAS Google Scholar - Kiemeney, L.A. et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).
Article CAS Google Scholar - Tuupanen, S. et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat. Genet. 41, 885–890 (2009).
Article CAS Google Scholar - Pomerantz, M.M. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).
Article CAS Google Scholar - Faumont, N. et al. c-Myc and Rel/NF-κB are the two master transcriptional systems activated in the latency III program of Epstein-Barr virus-immortalized B cells. J. Virol. 83, 5014–5027 (2009).
Article CAS Google Scholar - Ho, I.C., Tai, T.S. & Pai, S.Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat. Rev. Immunol. 9, 125–135 (2009).
Article CAS Google Scholar - Li, J., Qian, C.N. & Zeng, Y.X. Regulatory T cells and EBV associated malignancies. Int. Immunopharmacol. 9, 590–592 (2009).
Article CAS Google Scholar - Atayar, C. et al. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas. Am. J. Pathol. 166, 127–134 (2005).
Article CAS Google Scholar - La Rosa, F.A., Pierce, J.W. & Sonenshein, G.E. Differential regulation of the c-myc oncogene promoter by the NF-κB rel family of transcription factors. Mol. Cell. Biol. 14, 1039–1044 (1994).
Article CAS Google Scholar - Maurice, D., Hooper, J., Lang, G. & Weston, K. c-Myb regulates lineage choice in developing thymocytes via its target gene Gata3. EMBO J. 26, 3629–3640 (2007).
Article CAS Google Scholar - Papaemmanuil, E. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat. Genet. 41, 1006–1010 (2009).
Article CAS Google Scholar - Jundt, F. et al. Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease. Blood 99, 3060–3062 (2002).
Article CAS Google Scholar - Hjalgrim, H. & Engels, E.A. Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: a review of the epidemiological evidence. J. Intern. Med. 264, 537–548 (2008).
Article CAS Google Scholar - Stranger, B.E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005).
Article Google Scholar - Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).
Article CAS Google Scholar - Alexander, F.E. et al. An epidemiologic study of index and family infectious mononucleosis and adult Hodgkin's disease (HD): evidence for a specific association with EBV+ve HD in young adults. Int. J. Cancer 107, 298–302 (2003).
Article CAS Google Scholar - Jarrett, R.F. 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. 56, 811–816 (2003).
Article CAS Google Scholar - Willett, E.V., O'Connor, S., Smith, A.G. & Roman, E. Does smoking or alcohol modify the risk of Epstein-Barr virus-positive or -negative Hodgkin lymphoma? Epidemiology 18, 130–136 (2007).
Article Google Scholar - Penegar, S. et al. National study of colorectal cancer genetics. Br. J. Cancer 97, 1305–1309 (2007).
Article CAS Google Scholar - Hjalgrim, H. et al. Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res. 67, 2382–2388 (2007).
Article CAS Google Scholar - Smedby, K.E. et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J. Natl. Cancer Inst. 97, 199–209 (2005).
Article Google Scholar - Sorensen, K.M. et al. Whole genome amplification on DNA from filter paper blood spot samples: an evaluation of selected systems. Genet. Test. 11, 65–71 (2007).
Article CAS Google Scholar - van Leeuwen, F.E. et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J. Natl. Cancer Inst. 95, 971–980 (2003).
Article Google Scholar - Broeks, A. et al. Increased risk of breast cancer following irradiation for Hodgkin's disease is not a result of ATM germline mutations. Int. J. Radiat. Biol. 76, 693–698 (2000).
Article CAS Google Scholar - De Bruin, M.L. et al. Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J. Clin. Oncol. 27, 4239–4246 (2009).
Article Google Scholar - Lake, A. et al. Mutations of NFKBIA, encoding IκBα, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int. J. Cancer 125, 1334–1342 (2009).
Article CAS Google Scholar - Pettiti, D. Meta-analysis Decision Analysis and Cost-Effectiveness Analysis (Oxford University Press, Oxford, New York, 1994).
- Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
Article Google Scholar - Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005).
Article CAS Google Scholar - Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).
Article CAS Google Scholar - Matys, V. et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 34, D108–D110 (2006).
Article CAS Google Scholar - Ferretti, V. et al. PReMod: a database of genome-wide mammalian _cis_-regulatory module predictions. Nucleic Acids Res. 35, D122–D126 (2007).
Article CAS Google Scholar - Hallikas, O. et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124, 47–59 (2006).
Article CAS Google Scholar - Cuzick, J. Wilcoxon-type test for trend. Stat. Med. 4, 87–90 (1985).
Article CAS Google Scholar
Acknowledgements
Leukemia Lymphoma Research (UK) and Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) provided principal funding for the study. We acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre. This study made use of control genotyping data generated by the Wellcome Trust Case Control Consortium. 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 the project was provided by the Wellcome Trust under awards 076113 and 085475. At the Institute of Cancer Research, sample and data acquisition was supported by Breakthrough Breast Cancer and the European Union, and we acknowledge NHS funding to the NIHR Biomedical Research Centre. We are grateful to the patients and their clinicians who participated in this collection (Supplementary Note). Work at the Leukaemia Research Fund (LRF) Virus Centre was funded by Leukaemia and Lymphoma Research. Sample and data acquisition for the UK replication series was also supported by the Kay Kendall Leukaemia Fund. The Epidemiology and Genetics Lymphoma Case-Control Study (ELCCS) was funded by Leukaemia and Lymphoma Research. Grant support to the German Study Group was through Deutsche Krebshilfe and the EU, grant HEALTH-F4-2007-200767. The SCALE study is supported by the Lundbeck Foundation grant R19 A2364, the Danish Cancer Research Foundation grant 41-08 and the Danish Cancer Society grant DP 08155. At the Department of Pathology and Medical Biology, University of Groningen, sample and data acquisition was supported by two grants from the Dutch Cancer Society (RUG 200-2315 and RUG 2009-4313). The Netherlands Cancer Institute (NKI) study was supported by the Dutch Cancer Society (grants No. NKI 98-1833, NKI 04-3068, NKI 08-3994) and the EU 6th framework programme (project no. 012926). We thank A. Kesminiene for coordinating the EU-framework project, M. Schaapveld and A. Eggermond for data management and L. Braaf and I. Mikolajewska for lab assistance. We are indebted to the patients and physicians who participated in this collection (Supplementary Note).
Author information
Author notes
- Victor Enciso-Mora, Peter Broderick and Yussanne Ma: These authors contributed equally to this work.
Authors and Affiliations
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK
Victor Enciso-Mora, Peter Broderick, Yussanne Ma, Bianca Olver, Amy Lloyd, Sara E Dobbins, Jayaram Vijayakrishnan & Richard S Houlston - Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
Ruth F Jarrett, Lesley Shield, Annette Lake & Dorothy Montgomery - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Henrik Hjalgrim, Klaus Rostgaard & Mads Melbye - Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Kari Hemminki & Asta Försti - Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden
Kari Hemminki & Arjan Diepstra - Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
Anke van den Berg - Department of Health Sciences, Epidemiology and Genetics Unit, University of York, York, UK
Tracy Lightfoot & Eve Roman - Department of Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Flora E van Leeuwen & Marieke de Bruin - Department of Experimental Therapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Annegien Broeks - Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany
Andreas Engert, Elke Pogge von Strandmann & Katrin S Reiners - Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
Ilja M Nolte - Department of Medicine, Unit of Clinical Epidemiology, Karolinska University Hospital, Stockholm, Sweden
Karin E Smedby - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Hans-Olov Adami - Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
Hans-Olov Adami - Department of Radiotherapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Nicola S Russell - Department of Pathology and Oncology, Karolinska Institutet, Stockholm, Sweden
Bengt Glimelius - Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden
Bengt Glimelius - Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark
Stephen Hamilton-Dutoit - Department of Clinical Immunology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
Lars P Ryder - Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden
Daniel Molin - Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark
Karina Meden Sorensen - Cancer Prevention Institute of California, Fremont, California, USA
Ellen T Chang & Anthony J Swerdlow - Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA
Ellen T Chang - Cancer Immunogenetics Group, School of Cancer and Enabling Sciences, University of Manchester, Research Floor, St. Mary's Hospital, Manchester, UK
Malcolm Taylor - Section of Epidemiology, Institute of Cancer Research, Sutton, UK
Rosie Cooke - Department of Genetics University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
Robert Hofstra & Helga Westers - Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
Tom van Wezel & Ronald van Eijk - The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
Alan Ashworth
Authors
- Victor Enciso-Mora
- Peter Broderick
- Yussanne Ma
- Ruth F Jarrett
- Henrik Hjalgrim
- Kari Hemminki
- Anke van den Berg
- Bianca Olver
- Amy Lloyd
- Sara E Dobbins
- Tracy Lightfoot
- Flora E van Leeuwen
- Asta Försti
- Arjan Diepstra
- Annegien Broeks
- Jayaram Vijayakrishnan
- Lesley Shield
- Annette Lake
- Dorothy Montgomery
- Eve Roman
- Andreas Engert
- Elke Pogge von Strandmann
- Katrin S Reiners
- Ilja M Nolte
- Karin E Smedby
- Hans-Olov Adami
- Nicola S Russell
- Bengt Glimelius
- Stephen Hamilton-Dutoit
- Marieke de Bruin
- Lars P Ryder
- Daniel Molin
- Karina Meden Sorensen
- Ellen T Chang
- Malcolm Taylor
- Rosie Cooke
- Robert Hofstra
- Helga Westers
- Tom van Wezel
- Ronald van Eijk
- Alan Ashworth
- Klaus Rostgaard
- Mads Melbye
- Anthony J Swerdlow
- Richard S Houlston
Contributions
R.S.H. designed the study and obtained financial support. R.S.H. drafted the manuscript with contributions from P.B., V.E.-M., Y.M. and S.E.D. Y.M. and V.E.-M. performed statistical and bioinformatic analyses. P.B. performed sample coordination and laboratory analyses. B.O., Amy Lloyd and J.V. performed genotyping. A.J.S., A.A. and R.C. provided samples and data from a study conducted at the Institute of Cancer Research. E.R. initiated ELCCS. T.L., M.T. and E.R. managed and prepared Epidemiology and Genetics Lymphoma Case-Control Study samples. R.F.J. designed and conducted studies contributing to the UK replication series, and R.F.J., L.S., Annette Lake and Dorothy Montgomery prepared samples and collated data. F.E.v.L. designed the Dutch NKI study and obtained financial support. N.S.R. and M.d.B. were involved in identification and inclusion of Dutch cases, study design, review board approval and clinical implementation. A.B. coordinated collection and preparation of the NKI samples. A.F., K.H., A.E., E.P.v.S. and K.S.R. provided samples and data from German cases and controls. A.D., I.M.N. and A.v.d.B. collected samples and data from cHL cases ascertained through Groningen University. R.H., H.W., T.v.W. and R.v.E. performed ascertainment and collection of control samples from The Netherlands. H.H., M.M., K.R., L.P.R., K.E.S., H.-O.A., B.G., Daniel Molin, S.H.-D., K.M.S. and E.T.C. provided samples and data from the SCALE study in Denmark and Sweden. S.H.-D. analyzed samples and provided data from Danish cHL cases. All authors contributed to the final paper. R.F.J. and H.H. contributed equally to the paper and should be considered to have equal positional status in the author list.
Corresponding author
Correspondence toRichard S Houlston.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Enciso-Mora, V., Broderick, P., Ma, Y. et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3).Nat Genet 42, 1126–1130 (2010). https://doi.org/10.1038/ng.696
- Received: 30 June 2010
- Accepted: 30 September 2010
- Published: 31 October 2010
- Issue date: December 2010
- DOI: https://doi.org/10.1038/ng.696