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Cancer Res. 2018 Jul 15;78(14):4086-4096. doi: 10.1158/0008-5472.CAN-17-2900. Epub 2018 May 7.

HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

Author information

1
Department of Population Sciences, Beckman Research Institute and the City of Hope, Duarte, California. sowang@coh.org.
2
Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, and Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts.
3
Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
4
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
5
Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, California.
6
Department of Population Sciences, Beckman Research Institute and the City of Hope, Duarte, California.
7
Department of Medicine Solna, unit of clinical epidemiology, Karolinska Institutet, Stockholm, Sweden.
8
Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
9
Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
10
Department of Hematology, Rishospitalet, Copenhagen, Denmark.
11
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York.
12
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
13
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
14
Braun School of Public Health and Community Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
15
Centre for Big Data Research in Health, The University of New South Wales, Sydney, New South Wales, Australia.
16
Centre for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg, Germany.
17
Unit of Infections and Cancer, Cancer Epidemiology Research Programme, Institut Català d' Oncologia, IDIBELL, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
18
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
19
Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Departments of Preventive Medicine and Pathology, University of Southern California, Los Angeles, Calfornia.
20
Department of Pathology, School of Medicine and the UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama.
21
Department of Histopathology, Douglass Hanly Moir Pathology, Sydney, Australia.
22
Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
23
Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
24
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
25
Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island.
26
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
27
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
28
Division of Clinical Epidemiology, German Cancer Research Centre, Heidelberg, Baden-Württemberg, Germany.
29
Department of Health Sciences, University of York, York, United Kingdom.
30
Department of Pathology, City of Hope, Duarte, California.
31
Registry of Hematological Malignancies of Cote d'Or, INSERM UMR1231, University of Burgundy and Dijon University Hospital, Dijon, France.
32
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
33
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
34
Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
35
School of Public Health, Imperial College London, London, United Kingdom.
36
International Agency for Research on Cancer, Lyon, France.
37
Department of Immunology, CHU Henri Mondor, Créteil, France.
38
INSERM U 955, CHU Henri Mondor, Créteil, France.
39
Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa.
40
Center of Oncological Prevention (CPO) Piemonte and Unit of Medical Statistics and Epidemiology, Department Translational Medicine, University of Piemonte Orientale, Novara, Italy.
41
Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari, Italy.
42
Division of Hematology, S. Francesco Hospital, Nuoro, Italy.
43
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
44
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
45
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
46
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
47
Department of Obstetrics and Gynecology, New York University School of Medicine, New York City, New York.
48
Department of Environmental Medicine, New York University School of Medicine, New York City, New York.
49
Perlmutter Cancer Center, NYU Langone Medical Center, New York City, New York.
50
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
51
Department of Medicine, Stanford University School of Medicine, Stanford, Calfornia.
52
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
53
Bill Lyons Informatics Centre, UCL Cancer Institute, University College London, London, United Kingdom.
54
Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
55
Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris, France.
56
Université Paris Descartes, Paris, France.
57
Registre des hémopathies malignes de la Gironde, Institut Bergonié, University of Bordeaux, Inserm, Team EPICENE, UMR 1219, France.
58
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Cancer Research Center of Lyon, INSERM UMR1052, Center Léon Bérard, Lyon, France.
59
Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex, France.
60
Department of Hematology, Hospices Civils De Lyon, Centre Hospitalier Lyon-Sud and Université Claude Bernard, Lyon, France.
61
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York.
62
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, MF MU, Brno, Czech Republic.
63
School of Nursing and Human Sciences, Dublin City University, Dublin, Ireland.
64
Fred Hutchinson Cancer Research Center and School of Public Health and Community Medicine, University of Washington, Seattle, Washington.
65
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan.
66
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
67
Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
68
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California.
69
Sydney School of Public Health, The University of Sydney, Sydney, Australia.
70
Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
71
Department of Environmental Health Sciences, Yale School of Public Health, New Haven.
72
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
73
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

PMID:
29735552
PMCID:
PMC6065509
[Available on 2019-07-15]
DOI:
10.1158/0008-5472.CAN-17-2900
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