Polymorphisms in the Estrogen Receptor 1 and Vitamin C and Matrix Metalloproteinase Gene Families Are Associated with Susceptibility to Lymphoma

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. CONCLUSIONS/SIGNIFICANCE: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation

The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma

We are grateful to Paulo Vieira, Cecília Leão, Manuel T. Silva, Nuno Sousa, Jorge Correia- Pinto, Joana Palha, Margarida Correia-Neves, Margarida Lima and Matthew Berry for all their input throughout these studies and critical reading of the manuscript. We are grateful to the patients who joint this study as well as to all members of the Life and Health Sciences Research Institute and School of Health Sciences, University of Minho, who contributed in any way to the development of this workNon-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.AC, NSO, MTC, and AJA were financially supported by a fellowship from Fundação para a Ciência e Tecnologia, Portugal. MS is a Ciência 2007 fellow. This study was supported by Fundação para a Ciência e Tecnologia, Portugal (PIC/IC/83313/2007) and by Fundação Calouste Gulbenkian, Serviço de Saúde e Desenvolvimento Humano, Portugal (Grant Number:Proc/60666-MM/734). CFS, PB and LC were supported by National Institutes of Health (NIH) grants CA122663 and CA104682, and PB also by NIH grants CA45614 and CA89745

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

A population-based case–control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m−2 at five years before diagnosis,, was associated with an increased risk of NHL (OR=1.5, 95% CI 1.1–2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR=1.9, 95% CI 1.3–2.8). Genetic variants in the leptin (LEP 19G>A, LEP −2548G>A) and leptin receptor genes (LEPR 223Q>R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR=0.7, 95% CI 0.5–1.0) and increased with LEP −2548GA (OR=1.3, 95% CI 1.0–1.7) and −2548AA (OR=1.4, 95% CI 1.0–1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women

Dietary Acrylamide Intake and the Risk of Lymphatic Malignancies: The Netherlands Cohort Study on Diet and Cancer

BACKGROUND: Acrylamide, a probable human carcinogen, is present in many everyday foods. Since the finding of its presence in foods in 2002, epidemiological studies have found some suggestive associations between dietary acrylamide exposure and the risk of various cancers. The aim of this prospective study is to investigate for the first time the association between dietary acrylamide intake and the risk of several histological subtypes of lymphatic malignancies. METHODS: The Netherlands Cohort Study on diet and cancer includes 120,852 men and women followed-up since September 1986. The number of person years at risk was estimated by using a random sample of participants from the total cohort that was chosen at baseline (n =5,000). Acrylamide intake was estimated from a food frequency questionnaire combined with acrylamide data for Dutch foods. Hazard ratios (HRs) were calculated for acrylamide intake as a continuous variable as well as in categories (quintiles and tertiles), for men and women separately and for never-smokers, using multivariable-adjusted Cox proportional hazards models. RESULTS: After 16.3 years of follow-up, 1,233 microscopically confirmed cases of lymphatic malignancies were available for multivariable-adjusted analysis. For multiple myeloma and follicular lymphoma, HRs for men were 1.14 (95% CI: 1.01, 1.27) and 1.28 (95% CI: 1.03, 1.61) per 10 µg acrylamide/day increment, respectively. For never-smoking men, the HR for multiple myeloma was 1.98 (95% CI: 1.38, 2.85). No associations were observed for women. CONCLUSION: We found indications that acrylamide may increase the risk of multiple myeloma and follicular lymphoma in men. This is the first epidemiological study to investigate the association between dietary acrylamide intake and the risk of lymphatic malignancies, and more research into these observed associations is warranted

Post-GWAS Functional Characterization of Susceptibility Variants for Chronic Lymphocytic Leukemia

Recent genome-wide association studies (GWAS) have identified several gene variants associated with sporadic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Many of these CLL/SLL susceptibility loci are located in non-coding or intergenic regions, posing a significant challenge to determine their potential functional relevance. Here, we review the literature of all CLL/SLL GWAS and validation studies, and apply eQTL analysis to identify putatively functional SNPs that affect gene expression that may be causal in the pathogenesis of CLL/SLL. We tested 12 independent risk loci for their potential to alter gene expression through cis-acting mechanisms, using publicly available gene expression profiles with matching genotype information. Sixteen SNPs were identified that are linked to differential expression of SP140, a putative tumor suppressor gene previously associated with CLL/SLL. Three additional SNPs were associated with differential expression of DACT3 and GNG8, which are involved in the WNT/β-catenin- and G protein-coupled receptor signaling pathways, respectively, that have been previously implicated in CLL/SLL pathogenesis. Using in silico functional prediction tools, we found that 14 of the 19 significant eQTL SNPs lie in multiple putative regulatory elements, several of which have prior implications in CLL/SLL or other hematological malignancies. Although experimental validation is needed, our study shows that the use of existing GWAS data in combination with eQTL analysis and in silico methods represents a useful starting point to screen for putatively causal SNPs that may be involved in the etiology of CLL/SLL

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL