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

• Type of Material: Article
• Authors: Sophia S. Wang, Beckman Research Institute; Mary Carrington, Leidos Biomedical Research Inc.; Sonja I. Berndt, National Cancer Institute; Susan L. Slager, Mayo Clinic; Paige M. Bracci, University of California San Francisco; Jenna Voutsinas, Beckman Research Institute; James R. Cerhan, Mayo Clinic; Karin E. Smedby, Karolinska Institutet; Henrik Hjalgrim, Statens Serum Institut; Joseph Vijai, Memorial Sloan Kettering Cancer Center; Lindsay M. Morton, National Cancer Institute; Roel Vermeulen, Utrecht University; Ora Paltiel, Hadassah-Hebrew University; Claire M. Vajdic, University of New South Wales; Martha S. Linet, National Cancer Institute; Alexandra Nieters, University Medical Center Freiburg; Silvia de Sanjose, Institut Català d’ Oncologia; Wendy Cozen, University of Southern California; Elizabeth E. Brown, University of Alabama Birmingham; Jennifer Turner, Douglass Hanly Moir Pathology; Christopher R Flowers, Emory University; Christine F. Skibola, Emory University
• Language: English
• Date: 2018-07-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-17-2900
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 78
• Issue: 14
• Start Page: 4086
• End Page: 4096
• Grant/Funding Information: See Publication for full funding statement.
• Keywords: EPIDEMIOLOGIC RESEARCH; Oncology; CLASSIFICATION; INTERLYMPH; B-VIRUS INFECTION; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; Life Sciences & Biomedicine; NEOPLASMS; Science & Technology; HETEROZYGOTE ADVANTAGE; CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTIGENS
• Research Categories: Health Sciences, Oncology

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.