Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of three new genome-wide association studies (GWAS) and one prior scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of nine promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P=2.33×10 −21 ), rs2523607 at 6p21.33 (HLA-B; 2.40×10 −10 ), rs79480871 at 2p23.3 (NCOA1; P=4.23×10 −8 ), and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P=9.98×10 −13 and P=3.63×10 −11 , respectively). These data provide substantial new evidence for genetic susceptibility to this B-cell malignancy, and point towards pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL) 1 , has an aggressive clinical course 2 . The risk of DLBCL is increased in individuals with a family history of NHL (odds ratio (OR)=1.4; 95%CI 1.1-2.0) 3 , supporting a genetic contribution. Also, relatives of DLBCL patients are at elevated risk for both DLBCL (RR=9.8, and Hodgkin lymphoma (HL, RR=2.0, 95%CI 1.05-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to: James R. Cerhan, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905, Phone: 507.538.0499, Fax: 507.226.2478, cerhan.james@mayo.edu. 94 These authors contributed equally to this work. 95 These authors jointly directed this work. AUTHORS CONTRIBUTIONSJ.R.C., S.I.B., S.S.W., A.N., A.R.B.-W., Q.L., G. Severi, M. Melbye, L.R.T., M.P.P., C.L., B.M.B., S.L.S., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. organized and designed the study. J.R.C., L.C., L.B., A.H., P.M.B., E.A.H., S.L.S., G. Salles, C.F.S., N.R. and S.J.C. conducted and supervised the genotyping of samples. J.R.C., S.I.B., V.J., Z.W., M.Y., L.C., P.I.W.d.B., D.C., J.G., D. Zhi, Y.W.A., J.H., B.M., J.S., L.L., J.P., C.C.C., N.C., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. contributed to the design and execution of statistical analysis. J.R.C., S.I.B., V.J., H.G., J.M., S.S.W., Z.W., M.Y., L.C., A.N., D.C., A.M., C.R.F., A.J.D.R., C.L., K.E.S., C.F.S., N.R. and S.J.C. wrote the first draft of the manuscript. J.R.C., V.J., H.G., J.M., S.S.W., L.C., A.N., L.B., A.M., A.R.B.-W., Q.L., G. Severi, M. Melbye, J.G., R.D.J., E.K., L.R.T., M.P.P., C.M.V., J.J.S., G.G.G., D.A., R.S.K., M.Z., K.A.B., A.Z.-J., T.M.H., B.K.L., A.J.N., A.D., Y.W.A., M.L., C.A.T., S.M.A., T.E.W., G.J.W., A.S.V., D. Zelenika, H.T., C.H., T.J.M., H.H., B.G., H.-O.A., P.M.B., J.R., M.T.S., E.A.H., W.C., P.H., L.M.M., R.K.S., L.F.T., K.E.N., N.B., Y...

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The European Hematology Association Roadmap for European Hematology Research: a consensus document

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