Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common form of non-Hodgkin lymphoma (NHL) that occurs worldwide. To discover risk factors and pathogenesis of DLBCL, we performed the largest GWAS of DLBCL to date in samples of East Asian ancestry, consisting of 2,888 patients with DLBCL and 12,458 controls. The meta-analysis identified three novel loci, rs2233434 on 6p21.1 (OR = 1.26, P = 1.17 × 10−8), rs11066015 on 12q24.12 (OR = 1.24, P = 6.57 × 10−9) and rs6032662 on 20q13.12 (OR = 1.24, P = 5.22 × 10−12). Fine mapping analysis revealed that the extensive association within the MHC region was driven by two novel HLA alleles, HLA-A*02 and HLA-DQB1*03. Functional annotation, eQTL and colocalization analyses of the susceptibility loci implicated NFKBIE/TCTE1, ALDH2/BRAP and CD40 as candidate disease genes. The pleiotropic effect analysis of the DLBCL loci revealed shared genetic susceptibility between DLBCL and several autoimmune diseases. Our study also suggested genetic heterogeneity between Asian and European populations by identifying ancestry-specific genetic associations. Overall, this study has implicated novel disease genes and molecular mechanism for DLBCL.
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Data availability
The data have been deposited with links to BioProject accession number PRJCA029771 in the NCBI BioProject database https://www.ncbi.nlm.nih.gov/bioproject/.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
Miranda-Filho A, Pineros M, Znaor A, Marcos-Gragera R, Steliarova-Foucher E, Bray F. Global patterns and trends in the incidence of non-Hodgkin lymphoma. Cancer Causes Control. 2019;30:489–99.
Bassig BA, Au WY, Mang O, Ngan R, Morton LM, Ip DK, et al. Subtype-specific incidence rates of lymphoid malignancies in Hong Kong compared to the United States, 2001-2010. Cancer Epidemiol. 2016;42:15–23.
Goldin LR, Bjorkholm M, Kristinsson SY, Turesson I, Landgren O. Highly increased familial risks for specific lymphoma subtypes. Br J Haematol. 2009;146:91–4.
Berndt SI, Vijai J, Benavente Y, Camp NJ, Nieters A, Wang Z, et al. Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes. Leukemia. 2022;36:2835–44.
Smedby KE, Foo JN, Skibola CF, Darabi H, Conde L, Hjalgrim H, et al. GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet. 2011;7:e1001378.
Zelenetz AD, Gordon LI, Chang JE, Christian B, Abramson JS, Advani RH, et al. NCCN Guidelines(R) Insights: B-Cell Lymphomas, Version 5.2021. J Natl Compr Canc Netw. 2021;19:1218–30.
Tan DE, Foo JN, Bei JX, Chang J, Peng R, Zheng X, et al. Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population. Nat Genet. 2013;45:804–7.
Cerhan JR, Berndt SI, Vijai J, Ghesquieres H, McKay J, Wang SS, et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet. 2014;46:1233–8.
Kleinstern G, Yan H, Hildebrandt MAT, Vijai J, Berndt SI, Ghesquieres H, et al. Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways. Hum Mol Genet. 2020;29:70–9.
Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun. 2017;8:1826.
Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A, Platteel 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. 2007;110:3310–5.
Myouzen K, Kochi Y, Okada Y, Terao C, Suzuki A, Ikari K, et al. Functional variants in NFKBIE and RTKN2 involved in activation of the NF-kappaB pathway are associated with rheumatoid arthritis in Japanese. PLoS Genet. 2012;8:e1002949.
International Multiple Sclerosis Genetics C. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365:eaav7188.
Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44:1336–40.
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9.
International Multiple Sclerosis Genetics Consortium, Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013;45:1353–60.
Wang YF, Zhang Y, Lin Z, Zhang H, Wang TY, Cao Y, et al. Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nat Commun. 2021;12:772.
Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y, et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet. 2011;43:679–84.
Cui R, Kamatani Y, Takahashi A, Usami M, Hosono N, Kawaguchi T, et al. Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk. Gastroenterology. 2009;137:1768–75.
Ishigaki K, Akiyama M, Kanai M, Takahashi A, Kawakami E, Sugishita H, et al. Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases. Nat Genet. 2020;52:669–79.
McMaster ML, Berndt SI, Zhang J, Slager SL, Li SA, Vajdic CM, et al. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenstrom macroglobulinemia. Nat Commun. 2018;9:4182.
Labreche K, Daniau M, Sud A, Law PJ, Royer-Perron L, Holroyd A, et al. A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study. Neuro Oncol. 2019;21:1039–48.
Castaneda JM, Hua R, Miyata H, Oji A, Guo Y, Cheng Y, et al. TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa. Proc Natl Acad Sci USA. 2017;114:E5370–E8.
Pasqualucci L, Zhang B. Genetic drivers of NF-kappaB deregulation in diffuse large B-cell lymphoma. Semin Cancer Biol. 2016;39:26–31.
Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009;459:717–21.
Della-Valle V, Roos-Weil D, Scourzic L, Mouly E, Aid Z, Darwiche W, et al. Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice. Blood Cancer J. 2020;10:38.
Wang Q, Chang B, Li X, Zou Z. Role of ALDH2 in Hepatic Disorders: Gene Polymorphism and Disease Pathogenesis. J Clin Transl Hepatol. 2021;9:90–8.
Chang JS, Hsiao JR, Chen CH. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J Biomed Sci. 2017;24:19.
Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, Omori T, et al. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma. Carcinogenesis. 2002;23:1851–9.
Ozaki K, Sato H, Inoue K, Tsunoda T, Sakata Y, Mizuno H, et al. SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat Genet. 2009;41:329–33.
Zhang F, Liu C, Xu Y, Qi G, Yuan G, Cheng Z, et al. A two-stage association study suggests BRAP as a susceptibility gene for schizophrenia. PLoS One. 2014;9:e86037.
Liao YC, Wang YS, Guo YC, Ozaki K, Tanaka T, Lin HF, et al. BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis. Mol Med. 2011;17:1065–74.
Alasoo K, Rodrigues J, Danesh J, Freitag DF, Paul DS, Gaffney DJ. Genetic effects on promoter usage are highly context-specific and contribute to complex traits. Elife. 2019;8:e41673.
Clark LB, Foy TM, Noelle RJ. CD40 and its ligand. Adv Immunol. 1996;63:43–78.
Skibola CF, Nieters A, Bracci PM, Curry JD, Agana L, Skibola DR, et al. A functional TNFRSF5 gene variant is associated with risk of lymphoma. Blood. 2008;111:4348–54.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
Acknowledgements
This project was supported by grants of the GDPH Supporting Fund for Talent Program (KJ01201907) and Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology (2019B121205005). This work was also supported by the Agency of Science, Technology and Research (A*STAR), Singapore (to JJL, LW, RD, KPN, CCK and JNF).
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JJL, DL, JL, JB and NR conceived and designed the study; QC drafted the manuscript with help from JJL; LW and QC performed GWAS statistical analyses and reported the results; LW, QC, KPN, RD and JJL performed functional annotation and interpreted the results; RD, KPN, NR and JB edited the manuscript; WT, BS, RP, GL, WYA, RHL, CCK, QZ, JNF, SL, FZ, XZ, XY, QL, SC, WJ, STL and WL participated in the contribution of data or analysis tools. All authors read, commented, and approved the manuscript.
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Cui, Q., Tan, W., Song, B. et al. Genetic susceptibility of diffuse large B-cell lymphoma: a meta genome-wide association study in Asian population. Leukemia 39, 694–702 (2025). https://doi.org/10.1038/s41375-024-02503-4
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DOI: https://doi.org/10.1038/s41375-024-02503-4