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

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肿瘤，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与外源性性激素暴露之间的关系，以解释这种性别差异，但结果各不相同，尚未对与NHL及其亚型风险相关的流行病学和遗传因素进行全面评估。我们的创新分析将利用NCI资金，利用我们基于人群的病例对照NHL研究（2055例，2081例对照）中已经收集的流行病学和遗传学数据：目标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)确定甾体生成相关基因的单核苷酸多态性（snp）或与性激素在相同的免疫相关生物学途径中起作用的基因，是否改变了目的1中因素与NHL及其亚型风险之间的关系。性激素基因中的snp包括雌激素受体（ESR）、细胞色素P450 17A1 （CYP17A1）、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)和淋巴毒素α (LTA)。NHL的风险也与身体质量指数（BMI）的增加和一些自身免疫性疾病有关，而这些疾病又与性激素的水平和循环有关。因此，BMI和自身免疫性疾病将被仔细评估为激素效应与NHL风险之间关联的潜在混杂因素和影响调节因素。简约的多变量无条件逻辑回归模型将用于获得作为相对风险估计的比值比。基因-环境相互作用将评估在相同生物学途径中起作用的基因的暴露和snp，例如妊娠相关因子，以及IL-10， TNF-1， ESR1和ESR2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)已经分析了生物学途径中146个基因的snp，这些基因可能与性激素和NHL易感性之间的关系有关；2)已经收集了丰富的流行病学数据，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，可用于评估主要影响、混淆和影响改变；5)病理确诊及WHO分类NHL亚型；6) InterLymph Consortium的数据将用于未来的分析，允许对罕见亚型和暴露进行分析。明确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，为未来的研究提出假设，并直接适用于筛查和预防方案，以减少NHL的发病率。

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.