Risk of non-Hodgkin lymphoma associated with occupational exposure to solvents,metals, organic dusts and PCBs (Australia)

Objective: Several studies have suggested that there is an occupational component to the causation of non-Hodgkin lymphoma (NHL). We aimed to use accurate means to assess occupational exposures to solvents, metals, organic dusts and polychlorinated biphenyls (PCBs) in a case-control study. Methods: Cases were incident NHLs during 2000 and 2001 in two regions of Australia. Controls were randomly selected from the electoral roll and frequency matched to cases by age, sex and region. A detailed occupational history was taken from each subject. For jobs with likely exposure to the chemicals of interest, additional questions were asked by telephone interview using modified job specific modules. An expert allocated exposures using the information in the job histories and the interviews. Odds ratios were calculated for each exposure adjusting for age, sex, region and ethnic origin. Results: 694 cases and 694 controls (70% and 45% respectively of those potentially eligible) participated. The risk of NHL was increased by about 30% for exposure to any solvent with a dose response relationship, subgroup analysis showed the finding was restricted to solvents other than benzene. Exposure to wood dust also increased the risk of NHL slightly. Exposures to other organic dusts, metals, and PCBs were not strongly related to NHL. Conclusions: The risk of NHL appears to be increased by exposure to solvents other than benzene and possibly to wood dust

Hepatitis C and Non-Hodgkin Lymphoma Among 4784 Cases and 6269 Controls From the International Lymphoma Epidemiology Consortium

Background & Aims: increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin's lymphoma (NHL) subtypes after HCV infection. Methods: The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded. Results: HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40 -2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44-4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.682.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14-5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65-1.60). Conclusions: These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma)

Blood transfusion history and risk of non-Hodgkin lymphoma : an InterLymph pooled analysis

PURPOSE: To conduct a pooled analysis assessing the association of blood transfusion with risk of non-Hodgkin lymphoma (NHL). METHODS: We used harmonized data from 13 case-control studies (10,805 cases, 14,026 controls) in the InterLymph Consortium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusted for study design variables. RESULTS: Among non-Hispanic whites (NHW), history of any transfusion was inversely associated with NHL risk for men (OR 0.74; 95% CI 0.65-0.83) but not women (OR 0.92; 95% CI 0.83-1.03), pheterogeneity = 0.014. Transfusion history was not associated with risk in other racial/ethnic groups. There was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion, and further adjustment for socioeconomic status, body mass index, smoking, alcohol use, and HCV seropositivity did not alter the results. Associations for NHW men were stronger in hospital-based (OR 0.56; 95% CI 0.45-0.70) but still apparent in population-based (OR 0.84; 95% CI 0.72-0.98) studies. CONCLUSIONS: In the setting of a literature reporting mainly null and some positive associations, and the lack of a clear methodologic explanation for our inverse association restricted to NHW men, the current body of evidence suggests that there is no association of blood transfusion with risk of NHL

Smoking, Variation In N-acetyltransferase 1 (nat1) And 2 (nat2), And Risk Of Non-hodgkin Lymphoma: A Pooled Analysis Within The Interlymph Consortium

Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2. We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case-control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models. Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07-1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95-1.69) acetylators (p (interaction) = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes. The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes

The Future Colorectal Cancer Burden Attributable to Modifiable Behaviors: A Pooled Cohort Study

Background: Previous estimates of the colorectal cancer (CRC) burden attributed to behaviors have not considered joint effects, competing risk, or population subgroup differences. Methods: We pooled data from seven prospective Australian cohort studies (n ¼ 367 058) and linked them to national registries to identify CRCs and deaths. We estimated the strength of the associations between behaviors and CRC risk using a parametric piecewise constant hazards model, adjusting for age, sex, study, and other behaviors. Exposure prevalence was estimated from contemporary National Health Surveys. We calculated population attributable fractions for CRC preventable by changes to current behaviors, accounting for competing risk of death and risk factor interdependence. Statistical tests were two-sided. Results: During the first 10 years of follow-up, there were 3471 incident CRCs. Overweight or obesity explained 11.1%, ever smoking explained 10.7% (current smoking 3.9%), and drinking more than two compared with two or fewer alcoholic drinks per day explained 5.8% of the CRC burden. Jointly, these factors were responsible for 24.9% (95% confidence interval [CI] ¼ 19.7% to 29.9%) of the burden, higher for men (36.7%) than women (13.2%, Pdifference < .001). The burden attributed to these factors was also higher for those born in Australia (28.7%) than elsewhere (16.8%, Pdifference ¼ .047). We observed modification of the smoking-attributable burden by alcohol consumption and educational attainment, and modification of the obesity-attributable burden by age group and birthplace. Conclusions: We produced up-to-date estimates of the future CRC burden attributed to modifiable behaviors. We revealed novel differences between men and women, and other high–CRC burden subgroups that could potentially benefit most from programs that support behavioral change and early detection.This work was supported by the Australian National Health and Medical Research Council (NHMRC; ID1060991). The Australian NHMRC also supported Dr. Laaksonen (ID1053642), Prof. Canfell (ID1082989), Prof. Banks (ID1042717), Prof. Shaw (ID1079438), and Prof. Magliano (ID1118161). Dr. Laaksonen was additionally supported by the Cancer Institute of New South Wales (ID13/ECF/1-07). Ms. Arriaga was supported by an Australian Postgraduate Award and a Translational Cancer Research Network PhD Scholarship Top-up Award

The burden of cancer attributable to modifiable risk factors: The Australian cancer-PAF cohort consortium

Purpose To estimate the Australian cancer burden attributable to lifestyle-related risk factors and their combinations using a novel population attributable fraction (PAF) method that accounts for competing risk of death, risk factor interdependence and statistical uncertainty. Participants 365 173 adults from seven Australian cohort studies. We linked pooled harmonised individual participant cohort data with population-based cancer and death registries to estimate exposure-cancer and exposure-death associations. Current Australian exposure prevalence was estimated from representative external sources. To illustrate the utility of the new PAF method, we calculated fractions of cancers causally related to body fatness or both tobacco and alcohol consumption avoidable in the next 10 years by risk factor modifications, comparing them with fractions produced by traditional PAF methods. Findings to date Over 10 years of follow-up, we observed 27 483 incident cancers and 22 078 deaths. Of cancers related to body fatness (n=9258), 13% (95% CI 11% to 16%) could be avoided if those currently overweight or obese had body mass index of 18.5–24.9 kg/m2. Of cancers causally related to both tobacco and alcohol (n=4283), current or former smoking explains 13% (11% to 16%) and consuming more than two alcoholic drinks per day explains 6% (5% to 8%). The two factors combined explain 16% (13% to 19%): 26% (21% to 30%) in men and 8% (4% to 11%) in women. Corresponding estimates using the traditional PAF method were 20%, 31% and 10%. Our PAF estimates translate to 74 000 avoidable body fatness-related cancers and 40 000 avoidable tobacco- and alcohol-related cancers in Australia over the next 10 years (2017–2026). Traditional PAF methods not accounting for competing risk of death and interdependence of risk factors may overestimate PAFs and avoidable cancers. Future plans We will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities.This study was funded by the National Health and Medical Research Council (ID1060991; ID1053642 to MAL; ID1082989 to KC; ID1042717 to EB) and a Cancer Institute New South Wales Fellowship (ID13/ECF/1-07 to MAL). Maria Arriaga was supported by Australian Postgraduate Award and a Translational Cancer Research Network (TCRN) PhD Scholarship Top-up Award

Common Gene Variants in the Tumor Necrosis Factor (TNF) and TNF Receptor Superfamilies and NF-kB Transcription Factors and Non-Hodgkin Lymphoma Risk

BACKGROUND:A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF) (TNF G-308A) is associated with increased non-Hodgkin lymphoma (NHL) risk. The protein product, TNF-alpha, activates the nuclear factor kappa beta (NF-kappaB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-kappaB pathways are important for NHL and that gene variations across the pathways may alter NHL risk. METHODOLOGY/PRINCIPAL FINDINGS:We genotyped 500 tag single nucleotide polymorphisms (SNPs) from 48 candidate gene regions (defined as 20 kb 5', 10 kb 3') in the TNF and TNF receptor superfamilies and the NF-kappaB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtained a gene region-level summary of association by computing the minimum p-value ("minP test"). We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-kappaB pathway and NHL (p = 0.02). We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL) (p-trend = 0.001). We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024), IRF4 rs12211228 (p-trend = 0.0026), TNFSF13B rs2582869 (p-trend = 0.0055), TANK rs1921310 (p-trend = 0.0025), TNFSF7 rs16994592 (p-trend = 0.0024), and TNFRSF13C rs6002551 (p-trend = 0.0074). All associations were consistent in each study with no apparent specificity for NHL subtype. CONCLUSIONS/SIGNIFICANCE:Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response