Epigenetic Age as a Marker of Reproductive Age and Modifier of Invasive Breast Cancer Risk Among Postmenopausal Women

表观遗传年龄作为绝经后妇女生育年龄的标志和侵袭性乳腺癌风险的调节因素

• 批准号: 9976475
• 负责人: Alexandra Margaret Lynn Binder
• 金额: $ 14.57万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976475
• 关键词: Acceleration; Age; Age at First Live Birth; Age at Menarche; Aging; Alcoholic beverage heavy drinker; Bilateral oophorectomy; Bioavailable; Biological; Biological Aging; Biology; Blood; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Feeding; Cancer Control; Cell physiology; Cells; Chronology; Clinical; Clinical Trials; Color; Contraceptive Usage; DNA Methylation; Development Plans; Disease; Endometrial Carcinoma; Environmental Exposure; Environmental Impact; Epidemiologist; Epigenetic Process; Estradiol; European; Family history of; First Births; Gene Expression Regulation; Goals; Health; Healthcare; Hormonal; Hormones; Incidence; Interdisciplinary Study; Investigation; Knowledge; Life Cycle Stages; Life Style; Malignant Neoplasms; Malignant neoplasm of ovary; Measurement; Measures; Mediating; Menarche; Menopause; Mentorship; Methodology; Modification; Obesity; Observational Study; Oral Contraceptives; Pattern; Postdoctoral Fellow; Postmenopause; Premature Menopause; Prevention strategy; Process; Puberty; Publications; Reporting; Reproductive History; Reproductive Process; Research; Research Institute; Research Personnel; Research Project Grants; Risk; Risk Factors; Scientist; Smoker; Subgroup; Testosterone; Time; Translating; Variant; Whole Blood; Woman; Women' s Health; Work; behavior influence; cancer biomarkers; cancer invasiveness; cancer prevention; cancer risk; career; clinically relevant; cohort; deviant; disorder prevention; experience; genome-wide; hazard; high risk; hormone therapy; improved; in utero; innovation; insight; lifestyle factors; malignant breast neoplasm; mortality; parity; reproductive; reproductive senescence; risk prediction model

Dr. Binder's goal is to become a leading academic epidemiologist in the epigenetic programming of health and disease, with an emphasis on hormonally responsive cancer risk. She plans to apply innovative methodological approaches to efficiently capture biologically meaningful changes in gene regulation. Dr. Binder will collaborate with a broad spectrum of scientists to translate insight from these mechanistic studies into improvements in health care and disease prevention. Her research thus far has focused on determinants of epigenetic patterns established in utero and during puberty. The proposed research project will bridge this experience to study the impact of epigenetic modifications acquired across the life course on postmenopausal breast cancer incidence. Epigenetic age is a predictor of health and an indicator of biological aging, capturing the cumulative impact of environmental and behavioral influences across time on cellular function. Prior studies have suggested a positive correlation between epigenetic aging and cancer risk. Paradoxically, aspects of reproductive history suggested to decelerate epigenetic age are associated with increased breast cancer incidence. Therefore we hypothesize there is a clinically relevant interaction between epigenetic age and the process of reproductive aging on hormonally responsive cancer risk among postmenopausal women. We propose analyzing epigenetic age acceleration (AgeAccel; deviance between chronological and epigenetic age) within 5,406 postmenopausal women from the Women's Health Initiative Observational Study and Clinical Trial with previously measured genome-wide DNA methylation in whole blood. This will include a subset of 1,382 women with bioavailable estradiol measurements, and 285 cases of invasive breast cancer. We plan to (1) characterize the variation in AgeAccel associated with reproductive history, (2) assess how AgeAccel is influenced by lifestyle factors, (3) analyze the association between AgeAccel and bioavailable estradiol and testosterone, (4) investigate how these hormones may mediate and interact with modifiable and unmodifiable predictors of cancer risk to impact AgeAccel, and (5) estimate the association between AgeAccel and breast cancer hazard. Together these aims will separate the influences on biological aging from chronological age relevant for cancers associated with reproductive history among postmenopausal women. Additionally, this work will appraise the utility of AgeAccel to track the change in risk profile over time. To conduct this research, Dr. Binder will build her substantive knowledge of aging and postmenopausal health through organized mentorships, didactic coursework, affiliations with interdisciplinary research institutes and associated seminars. Furthermore, Dr. Binder will generate new research partnerships with experts in cancer control and prevention to inform her analytic approach and interpretations. This development plan will build Dr. Binder's reputation in the epigenetic programming of women's health and cancer risk through publications and presentations, increase her network of collaborators, and fuel the submission of a research grant to further her career as an independent investigator in this field.

Binder博士的目标是成为健康和健康表观遗传学编程方面的领先学术流行病学家 疾病，重点是荷尔蒙反应的癌症风险。她计划应用创新的方法 有效捕捉基因调控中具有生物学意义的变化的方法。Binder博士将合作 与广泛的科学家一起将这些机械研究的洞察力转化为 保健和疾病预防。到目前为止，她的研究主要集中在表观遗传模式的决定因素上 在子宫和青春期建立的。拟议的研究项目将把这一经验联系起来，研究 生命过程中获得的表观遗传修饰对绝经后乳腺癌发病率的影响。 表观遗传年龄是健康的预测指标和生物老化的指标，反映了 随着时间推移，环境和行为对细胞功能的影响。此前的研究表明， 表观遗传老化与癌症风险的相关性。矛盾的是，生育史的某些方面表明 减慢表观遗传年龄与乳腺癌发病率的增加有关。因此我们假设 在临床上，表观遗传年龄和生殖衰老过程之间存在相互作用。 绝经后妇女对激素敏感的癌症风险。我们建议分析表观遗传年龄 绝经后5,406岁内加速(年龄加速；年龄与表观遗传年龄之间的偏差) 来自妇女健康倡议的妇女观察研究和临床试验，以前测量过 全血中的全基因组DNA甲基化。这将包括1,382名服用生物可用药的妇女 雌二醇测定，以及285例浸润性乳腺癌。我们计划(1)描述以下变化： AgeAccel与生育史相关，(2)评估AgeAccel如何受到生活方式因素的影响，(3) 分析AgeAccel与生物可利用的雌二醇和睾酮之间的关系，(4)调查这些因素是如何 荷尔蒙可能调节和影响癌症风险的可修改和不可修改的预测因素，并与其相互作用 AgeAccel，以及(5)估计AgeAccel和乳腺癌风险之间的关联。把这些目标放在一起 将把对生物衰老的影响与与癌症相关的时间年龄分开 绝经后妇女的生育史。此外，本工作还将对AgeAccel的实用性进行评估 以跟踪风险概况随时间的变化。为了进行这项研究，Binder博士将建立她的实质性 通过有组织的导师指导、授课课程、从属关系了解老龄化和绝经后健康 与跨学科研究机构和相关研讨会合作。此外，Binder博士将产生新的 与癌症控制和预防专家建立研究伙伴关系，为她的分析方法和 解读。这一发展计划将建立Binder博士在表观遗传编程方面的声誉 妇女健康和癌症风险通过出版物和演示文稿，增加她的合作者网络， 并提交研究补助金，以促进她作为这一领域的独立调查员的职业生涯。