Breast Cancer Risk Factors and Epigenetic Age Acceleration

技术摘要 在美国，癌症是第二大死因，乳腺癌(BRCA)是最主要的死因 在女性中被诊断为恶性肿瘤，是导致癌症死亡的第二大原因。尽管总体水平较低 发病率，非裔美国人(AA)女性患BRCA的年龄较早，且有明显较高的发病率 与被诊断患有BRCA的白人女性相比，死亡率。尽管筛查、获取和治疗可能 尽管这一差距在一定程度上是造成这种差距的原因，但很明显，在这些差距的背后还有其他机制。 一项新的研究表明，表观遗传图谱中的种族差异可能是解释 BRCA。 流行病学研究已经确定了许多与发生BRCA风险相关的因素。 荷尔蒙因素，如产次、第一次出生的年龄、初潮年龄和口服避孕药的使用，都有良好的效果。 已建立与BRCA风险的关联。许多其他因素也与BRCA风险有关，包括 体重指数(BMI)、体力活动、家族史和特定的遗传风险变异。但是，更多 需要研究来确定这些公认的风险因素的潜在生物学途径 BRCA风险。有趣的是，文献中的数据表明，这些风险因素的影响因种族而异， 与白人人群相比，AA人群对BRCA风险的影响更小或更大。 表观遗传变异，包括DNA甲基化，是对DNA的修饰，既是可遗传的，也是 基于环境变化的变量。因此，表观遗传机制可能代表了基因之间的联系 和环境风险因素，这些因素是BRCA发展的基础，也可能解释 乳腺癌危险因素的影响。两个独立的研究小组最近发现，DNA甲基化 基于整个基因组中的几个标记，有力地预测了一个人的实际年龄和 这样就捕捉到了生物衰老的“表观遗传时钟”。研究表明，“表观遗传年龄加速”-- 甲基化之间的差异--预测年龄和实际年龄--始终与总体年龄相关 死亡率和包括癌症在内的许多与年龄有关的疾病。进一步的研究表明，表观遗传衰老速度 与种族、性别以及已知的癌症风险因素(如吸烟和肥胖)密切相关， 提供了第一个人类证据表明与衰老相关的表观遗传过程是潜在的分子 种族健康差异的基础。 在这个项目中，我们将进行一个试点项目，研究表观遗传年龄对效果的影响 BRCA的已知环境和生活方式风险因素，因为它与乳腺癌风险有关，然后进行测试，以了解 如果他们因种族不同而不同。我们将通过乳房组织和血液的甲基化分析来测量表观遗传年龄 评估(1)血液表观遗传年龄与乳房组织表观遗传年龄相关的能力；(2)评估差异 按种族和(3)提供乳房表观遗传年龄与乳腺癌风险相关性的初步数据 各种因素。 这项建议将为扩大这一调查思路提供重要的初步数据 环境、遗传和表观遗传因素在BRCA致癌和BRCA差异中的作用。样品 本项目包括来自一项大型BRCA病例对照研究，包括社会经济状况和 从Case CCC集水区招募的不同种族的患者组。这项建议将有助于 为更大的R01级拨款生成必要的试点数据，以便更充分地研究这一重要的调查路线。

TECHNICAL ABSTRACT Cancer is the second leading cause of death in the United States, and breast cancer (BrCa) is the most diagnosed malignancy among women, and the second highest cause of cancer deaths. Despite lower overall incidence, African American (AA) women experience an earlier age of onset of BrCa and have significantly higher mortality rates compared to white women diagnosed with BrCa. Although screening, access and treatment may contribute to some of this disparity, it is clear that there are additional mechanisms underlying these disparities. New research suggests that racial differences in epigenetic profiles may be crucial for explaining inequalities of BrCa. Epidemiological studies have identified numerous factors associated with risk of developing BrCa. Hormonal factors, such as parity, age at first birth, age at menarche and oral contraceptive use, all have well established associations with BrCa risk. A number of other factors are also associated with BrCa risk, including body mass index (BMI), physical activity, family history, and specific genetic risk variants. However, additional research is needed to determine the underlying biological pathways of these well-established risk factors with BrCa risk. Interestingly, data in the literature suggests that effects of these risk factors differ by race, having smaller or larger effects on BrCa risk in AA populations compared to white populations. Epigenetic variants, including DNA methylation, are modifications to DNA that are both heritable and variable based on environmental variation. Epigenetic mechanisms thus may represent a link between genetic and environmental risk factors that underlie the development of BrCa, and also may explain racial differences in effect of risk factors for breast cancer. Two independent groups have recently identified that DNA methylation based on a handful of markers throughout the genome robustly predicts an individual’s chronological age and thus captures the ‘epigenetic clock’ for biological aging. It has been shown that ‘epigenetic age acceleration’ – the difference between methylation-predicted age and chronological age – is consistently associated with overall mortality and many age-related diseases including cancer. It has been further shown that epigenetic aging rates are significantly associated with race, sex, and with known cancer risk factors such as smoking and obesity, providing the first human evidence suggesting aging-related epigenetic processes are potential molecular underpinnings for racial health disparities. In this project, we will conduct a pilot project that will examine the impact of epigenetic age on the effect of known environmental and lifestyle risk factors for BrCa as it relates to breast cancer risk and then test to see if they differ by race. We will measure epigenetic age through methylation profiling of breast tissue and blood to evaluate (1) ability of blood epigenetic age to correlate with breast tissue epigenetic age; (2) assess differences by race and (3) to provide preliminary data on the correlation of breast epigenetic age with breast cancer risk factors. This proposal will provide the important preliminary data to expand this line of inquiry understanding environmental, genetic and epigenetic factors in BrCa carcinogenesis and BrCa disparities. The samples included in this project are from a large BrCa case-control study, and includes a socioeconomic status and racially diverse group of patients recruited from the Case CCC catchment area. This proposal will facilitate the generation of necessary pilot data for a larger R01 level grant to more fully study this important line of inquiry.