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

Abstract

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.