Non-Hodgkin lymphoma in women: reproductive, hormonal and genetic factors

描述（由申请人提供）：项目摘要/摘要女性非霍奇金淋巴瘤：生殖、激素和遗传因素非霍奇金淋巴瘤（NHL）是美国成年人中最常见的造血系统癌症，男性发病率高于女性（比例为1.4：1）。虽然有几项研究调查了生殖因素和外源性性激素暴露之间的关联，以解释这种性别差异，结果各不相同，并没有全面评估相关的流行病学和遗传因素相关的风险NHL和NHL亚型已进行。我们的创新分析将利用NCI的资金，通过使用我们的大型人群病例对照NHL研究中已经收集的流行病学和遗传学数据，（2055例，2081例对照）目的：1）确定女性内源性和外源性激素暴露是否与NHL和常见NHL亚型的风险相关;目的2）确定与类固醇生成相关的基因中的单核苷酸多态性（SNP）或与性激素在相同的免疫相关生物途径中起作用的基因中的SNP，改变Aim 1中的因子与NHL和NHL亚型风险之间的关联。感兴趣的性激素基因中的SNP包括雌激素受体（ESR）、细胞色素P450 17 A1（CYP 17 A1）、性激素结合球蛋白（SHBG）和儿茶酚-O-甲基转移酶（COMT），免疫/炎症途径中的SNP包括白细胞介素（IL）、核因子κ B（NF-：B）、肿瘤坏死因子α（TNF-1）和α-光敏素（LTA）。NHL的风险也与增加的身体质量指数（BMI）和一些自身免疫性疾病相关，每一种自身免疫性疾病又与性激素的水平和循环相关。因此，BMI和自身免疫性疾病将被仔细评估为激素效应和NHL风险之间相关性的潜在混杂因素和效应调节因子。将使用简约多变量非条件logistic回归模型获得比值比作为相对风险的估计值。将评价基因-环境相互作用的暴露和在相同生物学途径中发挥作用的基因中的SNP，例如妊娠相关因子，以及IL-10、TNF-1、ESR 1和ESR 2中的SNP。错误发现率方法将用于控制多重假设检验。该研究的主要优势在于：1）已经分析了可能与性激素和NHL易感性之间相关的生物学途径中146个基因的SNP的DNA; 2）已经收集了丰富的流行病学数据集，包括广泛的生殖史，性类固醇激素使用，自身免疫性疾病和BMI，可用于评估主效应，混杂效应和效应修正; 5）使用WHO分类进行病理学确认和NHL亚型分类; 6）将汇总数据用于InterLymph Consortium内的未来分析，以分析罕见亚型和暴露。阐明这些性激素相关因素在NHL风险中的作用将提高我们对淋巴瘤发生的理解，为未来的研究产生假设，并直接适用于筛查和预防计划，以减少NHL的发病率。 公共卫生相关性：非霍奇金淋巴瘤（NHL）的发病率在男性中高于女性，除了与严重免疫抑制和一些罕见遗传疾病相关的风险因素外，几乎没有其他风险因素。考虑到性激素影响免疫功能，女性和男性之间不同的生殖器相关暴露和条件可能有助于解释观察到的NHL性别差异。阐明生殖因素、雌激素相关疗法的使用与女性NHL和NHL亚型风险之间的关联，以及NHL风险与性相关激素之间的关系是否因激素代谢/产生和免疫功能中重要基因的变异而改变的分析，将提高我们对NHL发展的理解，有助于为未来的研究产生新的假设，并将直接适用于预防，干预和筛查计划，以降低NHL发病率。

DESCRIPTION (provided by applicant): Project Summary/Abstract Non-Hodgkin lymphoma in women: reproductive, hormonal and genetic factors Non-Hodgkin lymphoma (NHL) is the most common hematopoietic cancer in U.S. adults and has a higher incidence in men than in women (ratio of 1.4:1). Although several studies have investigated the association between reproductive factors and exogenous sex-hormone exposures to explain this sex differential, results have been varied and no comprehensive assessment of relevant epidemiologic and genetic factors related to risk of NHL and NHL subtypes has been conducted. Our innovative analyses will leverage NCI funding by using epidemiologic and genetic data already collected in our large population-based case-control NHL study (2055 cases, 2081 controls) to: Aim 1) determine whether endogenous and exogenous hormone exposures in women are associated with risk of NHL and common NHL subtypes and; Aim 2) determine whether single nucleotide polymorphisms (SNPs) in genes related to steroidogenesis or that function in the same immune- related biologic pathways as sex-hormones, alter the association between factors in Aim 1 and risk of NHL and NHL subtypes. SNPs in sex-hormone genes of interest include estrogen receptors (ESR), cytochrome P450 17A1 (CYP17A1), sex-hormone binding globulin (SHBG) and catechol-O-methyltransferase (COMT), and in immune/inflammatory pathways include interleukins (IL), nuclear factor kappa B (NF-:B), tumor necrosis factor alpha (TNF-1) and lymphotoxin alpha (LTA). Risk of NHL also has been associated with increased body mass index (BMI) and some autoimmune conditions with each in turn associated with levels and circulation of sex- hormones. Therefore, BMI and autoimmune conditions will be carefully assessed as potential confounders and effect modifiers of the association between hormonal effects and NHL risk. Parsimonious multivariable unconditional logistic regression models will be used to obtain odds ratios as estimates of relative risk. Gene- environment interactions will be evaluated for exposures and SNPs in genes that function in the same biologic pathways, e.g. pregnancy-related factors, and SNPs in IL-10, TNF-1, ESR1 and ESR2. False discovery rate methods will be used to control for multiple hypothesis testing. The study's major strengths are: 1) DNA already analyzed for SNPs in 146 genes in biologic pathways that may be relevant to the association between sex-hormone s and NHL susceptibility; 2) already collected rich epidemiologic dataset including extensive reproductive history, sex-steroid hormone use, autoimmune conditions and BMI available to evaluate main effects, confounding and effect modification; 5) pathological confirmation and NHL subtype classification using the WHO classification; 6) data will be pooled for future analyses within the InterLymph Consortium allowing analyses of rare subtypes and exposure. Clarifying the role of these sex-hormone related factors in NHL risk will improve our understanding of lymphomagenesis, generate hypotheses for future research and be directly applicable to screening and prevention programs to reduce NHL incidence. PUBLIC HEALTH RELEVANCE: Project Narrative Incidence of non-Hodgkin lymphoma (NHL) is higher in men than in women and few risk factors have been established other than those associated with severe immunosuppression and some rare genetic conditions. Given that sex-hormones impact immune function, it is plausible that hormonal-related exposures and conditions that differ between women and men may help explain the observed sex-difference in NHL. Analyses that clarify the association among reproductive factors, use of estrogen-related therapies and risk of NHL and NHL subtypes in women and whether the relationship between NHL risk and sex-related hormones is altered by variation in genes important in hormone metabolism/production and immune function will improve our understanding of NHL development, help to generate new hypotheses for future research and will be directly applicable to prevention, intervention and screening programs with a goal to reduce NHL incidence.