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

BackgroundNon-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 findings768 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/significanceOur findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation

Abstract B124: Genetic variants in sex hormone production, energy regulation and vitamin C and D uptake influence risk of non-Hodgkin's lymphoma

Abstract Infectious and autoimmune diseases associated with B-cell lymphomas involve inflammation, chronic activation and proliferation of lymphocytes. Since most lymphomas develop in the absence of any known chronic antigenic stimulation, genetic polymorphisms may provide alternative means to exert proinflammatory responses that fuel lymphoproliferation and promote B-cell growth and survival that contribute to lymphoma risk. We have previously reported associations between non-Hodgkin lymphoma (NHL) risk and genetic polymorphisms in pathways involving sex hormone synthesis/metabolism, energy regulation, and uptake and metabolism of dietary nutrients. To further corroborate the relevance of these pathways and to identify additional risk loci, we used data from our recent genome-wide association study of NHL (748 cases, 811 controls) and conducted focused candidate gene/pathway analyses. A number of SNPs in the estrogen related genes, ESR1, CYP17A1, CYP19A1, and HSD17B2, influenced risk of diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) in men and women. ESR1 encodes estrogen receptor 1 (ER) and regulates estrogen production by direct modulation of the CYP19A1 promoter. CYP17A1, CYP19A1 and HSD17B2 produce important enzymes involved in estrogen and testosterone synthesis. Estrogen and testosterone exert dose-dependent biphasic immunomodulatory effects. Thus, SNPs in these genes may mediate sex hormone levels and influence B-cell survival and growth characteristics, and possibly the potential for B-cells with pre-neoplastic lesions to undergo transformation. Several SNPs in LEP and/or LEPR, involved in energy regulation, were associated with risk of FL and DLBCL. Leptin, the LEP gene product, is a proinflammatory adipokine that once bound to its receptor (LEPR) exerts immune-mediated responses including pro-survival signals to B-cells. SNPs in the vitamin C (SLC23A2) and vitamin D (VDR) receptor genes were associated with FL risk. Vitamin C is an antioxidant that may play a key role in preventing oxidative-stress related DNA damage and genotoxicity to B-cells. Vitamin D inhibits proliferation and induces lymphocyte differentiation. An inverse association with lymphoma risk and UV exposure supports a role for low vitamin D in lymphomagenesis. These studies provide further evidence for the important roles of sex hormones, leptin, and vitamins C and D in the etiology of lymphoma. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B124.</jats:p

Polymorphisms in cytochrome P450 17A1 and risk of non-Hodgkin lymphoma

Polymorphisms in cytochrome P450 17A1 and risk of non-Hodgkin lymphoma Broad cross-talk exists between the endocrine and immune systems. Estrogen receptor expression in lymphocytes suggests that hormonal modulation may influence lymphoma risk. Analysis of genetic polymorphisms that affect oestrogen production, such as cytochrome P450 17A1 (CYP17A1) -34T>C, may provide insight into oestrogen's role in lymphomagenesis. CYP17A1 -34T>C and CYP17A1 IVS2 105A>C polymorphisms were analyzed in a non- Hodgkin lymphoma (NHL) population-based case-control study. The Cyp17A1 -34CC genotype was positively associated with NHL [odds ratio (OR) = 1.44, 95% confidence interval (0) 1.02-2.03], particularly diffuse large B-cell lymphoma (OR = 1.76, CI 1.14- 2.71). Associations of CYP17A1 polymorphisms with increased risk of NHL suggest a role for oestrogen in lymphomagenesis

Abstract 4717: A search for overlapping HLA risk loci between NHL and autoimmune diseases

Abstract Non-Hodgkin lymphoma (NHL) is a group of B- and T-cell neoplasms originating primarily from the lymph nodes, and represents the most common hematological malignancy in the United States. We recently conducted a genome-wide association study (GWAS) using DNA pools and identified a new risk locus for follicular lymphoma (FL) in the Class 1 human leukocyte antigen (HLA) region on chromosome 6. Currently, we are following up these results in a second GWAS using a subset of 757 NHL cases and 811 controls from a larger case-control study of NHL based in the San Francisco Bay Area using the Illumina HumanCNV370-Duo BeadChip. In the preliminary scan, we found additional evidence of Class 1 HLA loci that influence FL susceptibility, as well as loci in the Class 2 region, suggesting the importance of HLA genetic variation in FL risk. There is also clear evidence that HLA Class 1 and Class 2 loci confer genetic susceptibility to autoimmune diseases such as Crohn's disease (CD), type 1 diabetes (T1D), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Thus, because a history of autoimmune disease may increase risk of NHL, we explored whether HLA-region risk loci are common between these autoimmune diseases and NHL. Using genetic data available from the Wellcome Trust Case-Control Consortium (WTCCC) for CD and the software package BEAGLE 3.0.3, we imputed SNPs to look for association signals in the HLA region. SNPs were imputed based on CD genotyped SNPs and haplotype information from unrelated CEU samples in the HapMap phase II data. A Cochran-Armitage test for an additive genetic effect implemented in PLINK v1.05 was subsequently performed to test the genotype-phenotype associations of genotyped and imputed SNPs. Our preliminary results suggest associations in the HLA Class 2 region near the HLA-DQA2 and HLA-DQB2 genes, providing evidence that overlapping risk loci may exist between FL and CD. We are currently expanding our analysis to include genetic data for other autoimmune diseases available from WTCCC such as T1D and RA. These analyses will contribute new data about genetic variation in plausible HLA region pathways and will help to identify potentially functional genetic factors that contribute to lymphoma susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4717.</jats:p