Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium.
Abstract Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported. Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944,…
The Childhood Leukemia International Consortium
Abstract Background : Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is like…
Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most e…
Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project
Background: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. Methods: We pooled individual-level data from 20 case-control studies (17 471 NHL cases, 23 096 controls) from North Ame…
Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
International audience; 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-associa…
Childhood acute lymphoblastic leukaemia and birthweight: Insights from a pooled analysis of case–control data from Germany, the United Kingdom and the United States
Abstract Background Heavy birthweight is one of the few established risk factors for childhood acute lymphoblastic leukaemia (ALL). To provide new insight into this relationship, particularly at the extremes ( 4500 g), we pooled data from three of the largest childhood cancer case–control studies ever conducted. Methods Birthweight and gestational age on 4075 children with ALL and 12,065 controls were collected during the course of three studies conducted in the USA, the UK and Germany in the 1990s. Information was obtained from mothers at interview, and the impact of bias was evaluated using the UK study which accessed birth registrations of participants and non-participants. Odds ratios (…
A genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes
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…
A Pooled Analysis of Extremely Low-Frequency Magnetic Fields and Childhood Brain Tumors
Pooled analyses may provide etiologic insight about associations between exposure and disease. In contrast to childhood leukemia, no pooled analyses of childhood brain tumors and exposure to extremely low-frequency magnetic fields (ELF-MFs) have been conducted. The authors carried out a pooled analysis based on primary data (1960–2001) from 10 studies of ELF-MF exposure and childhood brain tumors to assess whether the combined results, adjusted for potential confounding, indicated an association. The odds ratios for childhood brain tumors in ELF-MF exposure categories of 0.1–<0.2 μT, 0.2–<0.4 μT, and ≥0.4 μT were 0.95 (95% confidence interval: 0.65, 1.41), 0.70 (95% CI: 0.40, 1.22), and 1.1…
Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study
A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF–MF) above 0.3 μT, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF–MF exposure categories and by 0.1 μT increases. The HRs by 0.1 μT increases were 1.00 (CI, 0.93–1.07) for event-free survival analysis and 1.04 (CI…
Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci.
Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as prim…
Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium
Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (…
Tumor necrosis factor (TNF) and lymphotoxin-a (LTA) polymorphisms and risk of non-hodgkin lymphoma in the interLymph consortium
In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF -308G>A (rs1800629), lymphotoxin-alpha (LTA) 252A>G (rs909253), IL10 -3575T>A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-…
Fetal growth and childhood acute lymphoblastic leukemia: Findings from the childhood leukemia international consortium
Positive associations have been reported between measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth – weight-for-gestational-age and proportion of optimal birth weight (POBW) – were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analy…
Non-Hodgkin lymphoma and obesity: A pooled analysis from the InterLymph consortium
Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL, self-reported anthropometric data on weight and height from over 10,000 cases of NHL and 16,000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m-2 or more, was not associated with NHL overall (pooled OR = 1.00, 95% confidence interval (CI) 0.70-1.41) or the majority of NHL …
Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.
International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional g…
A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus
Contains fulltext : 137763.pdf (Publisher’s version ) (Open Access) Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI)=0.76-0.86, Pcombined=3.5 x 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regul…
Survival from childhood acute lymphoblastic leukaemia in West Germany: Does socio-demographic background matter?
Sex, age, immunophenotype and white blood cell count at diagnosis are well accepted predictors of survival from acute lymphoblastic leukaemia (ALL) in children. Less is known about the relationship between socio-economic determinants and survival from paediatric ALL, studied here for the first time in German children.ALL cases were diagnosed between 1992 and 1994 and their parents interviewed during a previous nationwide case-control study. Children were followed-up for 10 years after diagnosis by the German Childhood Cancer Registry. Cox proportional hazards models estimating hazard ratios (HRs) were calculated to assess the impact of selected socio-demographic characteristics on overall a…
Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.
Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10 -20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10 -11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10 -10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10 -10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10 -8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRß1 multiallelic amino acids at p…
Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: Findings from the childhood leukemia international consortium
Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and t…
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
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.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cance…
Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
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 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 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; P = 2.40 × 10 '10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10 '8) and two independent SNPs, rs13255292 and rs47336…
A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma
Abstract Background: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein–Barr virus (EBV) status, particularly within the MHC region. Methods: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. Results: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interva…