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: 9754021
• 负责人: Alexandra Margaret Lynn Binder
• 金额: $ 7.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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 2019-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754021
• 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表观遗传编程的领先学术流行病学家和 疾病，重点是荷尔蒙反应式癌症风险。她计划应用创新的方法论 有效捕获基因调节的生物学意义变化的方法。 Binder博士将合作 通过广泛的科学家将这些机械研究的见解转化为改进 预防医疗保健和疾病。迄今为止，她的研究集中在表观遗传模式的决定因素上 在子宫内和青春期建立。拟议的研究项目将桥接这一经验，以研究 整个生命过程中获得的表观遗传修饰对绝经后乳腺癌发生的影响。 表观遗传时代是健康的预测指标，也是生物衰老的指标，捕获了累积的影响 环境和行为影响跨时间对细胞功能的影响。先前的研究表明阳性 表观遗传衰老与癌症风险之间的相关性。矛盾的是，提出了生殖历史的各个方面 减速表观遗传年龄与乳腺癌发病率增加有关。因此，我们假设 表观遗传年龄与生殖老化的过程之间存在临床相关的相互作用 绝经后妇女的荷尔蒙反应性癌症风险。我们建议分析表观遗传年龄 加速度（AGEACCEL；年代和表观遗传年龄之间的偏差）在5,406个绝经后 妇女来自妇女健康计划的观察性研究和临床试验先前测量 全基因组中的全基因组DNA甲基化。这将包括1,382名具有生物利用的妇女的子集 雌二醇测量和285例浸润性乳腺癌。我们计划（1）表征 与生殖历史相关的AgeAccel，（2）评估AgeAccel如何受到生活方式因素的影响，（3） 分析AgeAccel和可生物可利用雌二醇和睾丸激素之间的关联，（4）研究这些 激素可能会介导并与可修改和不可变化的癌症风险预测指标相互作用 AgeAccel，以及（5）估​​计AgeAccel与乳腺癌危害之间的关联。这些目标在一起 将将对生物衰老的影响与与癌症相关的年龄年龄分开 绝经后妇女的生殖历史。此外，这项工作将评估AgeAccel的实用性 跟踪风险概况随着时间的变化。为了进行这项研究，Binder博士将建立她的实质性 通过有组织的指导，教学课程，隶属关系了解老化和绝经后健康 与跨学科研究机构和相关研讨会。此外，Binder博士将生成新的 与癌症控制和预防专家的研究合作伙伴关系，以告知她的分析方法和 解释。该开发计划将建立Binder博士在表观遗传编程中的声誉 通过出版和演讲，妇女的健康和癌症风险，增加她的合作者网络， 并为研究赠款的提交助长了她在该领域的独立调查员的进一步职业。