HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

Sophia S. Wang*, Mary Carrington, Sonja I. Berndt, Susan L. Slager, Paige M. Bracci, Jenna Voutsinas, James R. Cerhan, Karin E. Smedby, Henrik Hjalgrim, Joseph Vijai, Lindsay M. Morton, Roel Vermeulen, Ora Paltiel, Claire M. Vajdic, Martha S. Linet, Alexandra Nieters, Silvia de Sanjose, Wendy Cozen, Elizabeth E. Brown, Jennifer TurnerJohn J. Spinelli, Tongzhang Zheng, Brenda M. Birmann, Christopher R. Flowers, Nikolaus Becker, Elizabeth A. Holly, Eleanor Kane, Dennis Weisenburger, Marc Maynadie, Pierluigi Cocco, Demetrius Albanes, Stephanie J. Weinstein, Lauren R. Teras, W. Ryan Diver, Stephanie J. Lax, Ruth C. Travis, Rudolph Kaaks, Elio Riboli, Yolanda Benavente, Paul Brennan, James McKay, Marie Hélène Delfau-Larue, Brian K. Link, Corrado Magnani, Maria Grazia Ennas, Giancarlo Latte, Andrew L. Feldman, Nicole Wong Doo, Graham G. Giles, Melissa C. Southey, Roger L. Milne, Kenneth Offit, Jacob Musinsky, Alan A. Arslan, Mark P. Purdue, Hans Olov Adami, Mads Melbye, Bengt Glimelius, Lucia Conde, Nicola J. Camp, Martha Glenn, Karen Curtin, Jacqueline Clavel, Alain Monnereau, David G. Cox, Hervé Ghesquières, Gilles Salles, Paulo Bofetta, Lenka Foretova, Anthony Staines, Scott Davis, Richard K. Severson, Qing Lan, Angela Brooks-Wilson, Martyn T. Smith, Eve Roman, Anne Kricker, Yawei Zhang, Peter Kraft, Stephen J. Chanock, Nathaniel Rothman, Patricia Hartge, Christine F. Skibola

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageAmerican English
Pages (from-to)4086-4096
Number of pages11
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - 15 Jul 2018
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported in part with funding from the NIH (R01CA179558 and R01CA33572).

Funding Information:
ATBC. The ATBC Study is supported by the Intramural Research Program of the U.S. NCI, NIH, and by U.S. Public Health Service contract HHSN261201500005C from the NCI, Department of Health and Human Services.

Funding Information:
CPS-II. The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples were supported by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the NCI Surveillance Epidemiology and End Results program.

Funding Information:
EpiLymph. European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006-023103); the Spanish Ministry of Health (grant references CIBERESP, PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10 and RTIC RD06/0020/0095), the Marató de TV3 Foundation (grant reference 051210), the Agència de Gestió d'Ajuts Universitarisi de Recerca–Generalitat de Catalunya (grant reference 2014SRG756) who had no role in the data collection, analysis or interpretation of the results; the NIH (contract NO1-CO-12400); the Compagnia di San Paolo–Programma Oncologia; the Federal Office for Radiation Protection grants StSch4261 and StSch4420, the JoséCarreras Leukemia Foundation grant DJCLS-R12/23, the German Federal Ministry for Education and Research (BMBF-01-EO-1303); the Health Research Board, Ireland and Cancer Research Ireland; Czech Republic supported by MH CZ – DRO (MMCI, 00209805) and MEYS–NPS I–LO1413; Fondation de France and Association de Recherche Contre le Cancer.

Funding Information:
FNLCR. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.

Funding Information:
GEC/Mayo GWAS. NIH (CA118444, CA148690, and CA92153). Intramural Research Program of the NIH, NCI. Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia and Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research, and the NIH (K08CA134919), National Center for Advancing Translational Science (UL1 TR000135).

Funding Information:
HPFS. The HPFS was supported in part by NIH grants CA167552, CA149445, and CA098122. We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Funding Information:
MCCS. The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553, and 504711 and

Funding Information:
MSKCC. Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE; U01 HG007033.

Funding Information:
NHS. The NHS was supported in part by NIH grants CA186107, CA87969, CA49449, CA149445, and CA098122. We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Funding Information:
NSW. NSW was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW, and the University of Sydney Faculty of Medicine.

Funding Information:
PLCO. This research was supported by the Intramural Research Program of the NCI and by contracts from the Division of Cancer Prevention, NCI, NIH, and DHHS.

Funding Information:
SCALE. Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institutet. Swedish Cancer Society grant (02 6661). NIH (5R01 CA69669-02); Plan Denmark.

Funding Information:
UCSF2. The UCSF studies were supported by the NCI, NIH, CA1046282 and CA154643. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the NCI's Surveillance, Epidemiology, and End Results

Publisher Copyright:
© 2018 American Association for Cancer Research.

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