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...

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

Objectives Several agricultural pesticides have shown a carcinogenic potential in experimental animals. Methods In 1998-2003, 2337 incident lymphoma cases and 2434 controls participated in the EPILYMPH case-control study in six European countries. A detailed occupational history was collected in cases and controls. Specifi c questions for farm workers included type of crop, farm size, pests being treated, type and schedule of pesticide use. We conducted a preliminary analysis of risk of lymphoma and its major subtypes associated with occupational exposure to groups of pesticides. The OR and its 95% CI was calculated with unconditional logistic regression for all lymphomas, and its major subtypes, adjusting by age, gender, and education. Results Lymphoma risk did not increase among those exposed to inorganic (OR = 1.3, 95% CI 0.9 to 1.7) or organic pesticides (OR = 1.1, 95% CI 0.9 to 1.4). Risk of CLL was signifi cantly increased among those exposed to pesticides (OR = 1.5 95% CI 1.0 to 2.2), and particularly to organophosphates (OR = 2.2, 95% CI 1.1 to 4.4). No other signifi cant associations were observed. Conclusions Our results confi rm previous reports of an increase in risk of specifi c lymphoma subtypes associated with exposure to specifi c agrochemicals.

Background: Benzene is an established leukemogen at high exposure levels. Although low-level benzene exposure is widespread and may induce oxidative damage, no mechanistic biomarkers are available to detect biological dysfunction at low doses.Objectives: Our goals were to determine in a large multicenter cross-sectional study whether low-level benzene is associated with increased blood mitochondrial DNA copy number (mtDNAcn, a biological oxidative response to mitochondrial DNA damage and dysfunction) and to explore potential links between mtDNAcn and leukemia-related epigenetic markers.Methods: We measured blood relative mtDNAcn by real-time polymerase chain reaction in 341 individuals selected from various occupational groups with low-level benzene exposures (> 100 times lower than the Occupational Safety and Health Administration/European Union standards) and 178 referents from three Italian cities (Genoa, Milan, Cagliari).Results: In each city, benzene-exposed participants showed higher mtDNAcn than referents: mtDNAcn was 0.90 relative units in Genoa bus drivers and 0.75 in referents (p = 0.019); 0.90 in Milan gas station attendants, 1.10 in police officers, and 0.75 in referents (p-trend = 0.008); 1.63 in Cagliari petrochemical plant workers, 1.25 in referents close to the plant, and 0.90 in referents farther from the plant (p-trend = 0.046). Using covariate-adjusted regression models, we estimated that an interquartile range increase in personal airborne benzene was associated with percent increases in mtDNAcn equal to 10.5% in Genoa (p = 0.014), 8.2% (p = 0.008) in Milan, 7.5% in Cagliari (p = 0.22), and 10.3% in all cities combined (p < 0.001). Using methylation data available for the Milan participants, we found that mtDNAcn was associated with LINE-1 hypomethylation (–2.41%; p = 0.007) and p15 hypermethylation (+15.95%, p = 0.008).Conclusions: Blood MtDNAcn was increased in persons exposed to low benzene levels, potentially reflecting mitochondrial DNA damage and dysfunction.

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.