Breast Cancer Risk Factors and Epigenetic Age Acceleration

技术摘要 癌症是美国第二大死亡原因，乳腺癌（BrCa）是最 在妇女中被诊断为恶性肿瘤，是癌症死亡的第二大原因。尽管总体较低 非洲裔美国人（AA）女性的BrCa发病年龄较早， 与诊断为BrCa的白色女性相比的死亡率。尽管筛查、获取和治疗可能 虽然这些差异在一定程度上是由其他因素造成的，但很明显，这些差异背后还有其他机制。 新的研究表明，表观遗传特征中的种族差异可能是解释遗传不平等的关键。 BrCa。 流行病学研究已经确定了许多与BrCa风险相关的因素。 激素因素，如产次、初次生育年龄、初潮年龄和口服避孕药的使用， 与BrCa风险的关联。许多其他因素也与BrCa风险相关，包括 身体质量指数（BMI），身体活动，家族史和特定的遗传风险变异。但是，额外的 需要进行研究以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， 与白色人群相比，AA人群对BrCa风险的影响较小或较大。 表观遗传变异，包括DNA甲基化，是对DNA的修饰，既可遗传， 基于环境变化的变量。因此，表观遗传机制可能代表了遗传学之间的联系。 和环境风险因素，这些因素是BrCa发展的基础，也可以解释BrCa的种族差异。 乳腺癌的危险因素。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少数标记，可以有力地预测个体的实际年龄， 从而捕获生物衰老的“表观遗传时钟”。已经证明“表观遗传年龄加速”- 甲基化预测年龄和实际年龄之间的差异-始终与总体 死亡率和许多与年龄有关的疾病，包括癌症。研究进一步表明，表观遗传衰老率 与种族、性别和已知的癌症风险因素（如吸烟和肥胖）显著相关， 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生物学过程。 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，将检查表观遗传年龄对效果的影响 已知的BrCa的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， 如果他们因种族而异。我们将通过乳腺组织和血液的甲基化谱来测量表观遗传年龄， 评价（1）血液表观遗传年龄与乳腺组织表观遗传年龄相关的能力;（2）评估差异 （3）提供关于乳腺表观遗传年龄与乳腺癌风险相关性的初步数据 因素 这一建议将提供重要的初步数据，以扩大这一调查线的理解 BrCa致癌作用和BrCa差异的环境、遗传和表观遗传因素。样品 本项目中包括的数据来自一项大型BrCa病例对照研究，包括社会经济状况和 从病例CCC集水区招募的不同种族的患者组。这项建议将促进 为更大的R 01级赠款生成必要的试点数据，以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.