Understanding the role of ovulatory cycles on ovarian cancer risk across the lifecourse and spectrum of risk

项目总结/摘要 美国每年诊断出超过22，000例卵巢癌新发病例，其中仅47.6% 生存超过五年。卵巢癌是最致命的妇科癌症，由于有几个 可改变的风险因素，没有有效的筛查工具，缺乏特定的症状， 复发卵巢癌的唯一预防指南是针对高危、绝经前妇女的 （BRCA 1/2携带者，或有乳腺癌和/或卵巢癌家族史的女性）考虑接受 在生育完成后进行双侧输卵管卵巢切除术以降低风险。没有官方的指导方针， 平均风险的女性该病的病因尚不清楚，但流行病学研究表明， 一致发现，中断排卵的事件可以预防卵巢癌的风险， 众所周知的“持续排卵”理论具体而言，产次（活产数较高）、口服避孕药的使用 避孕药和哺乳对卵巢癌有保护作用，而初潮年龄早， 绝经、不孕和未生育则有相反的效果。然而，通过这些机制， 排卵的开始和频率对癌症风险的影响尚不清楚。一种可能性是， 由于排卵期间的炎症，每个排卵周期都会增加致癌突变 从而改变微环境，促进DNA损伤和癌细胞的生长。使用两个良好的- 具有深度表型、临床和遗传数据的特征化大型队列（英国生物库和 乳腺癌家族登记），我们将使用一种新的生命过程流行病学方法来调查如何在乳腺癌家族登记。 早期生活事件（初潮年龄）和长期暴露（一生中的排卵周期（IVF），总结 与考虑的生殖事件相比，可以更好地捕获累积排卵暴露的措施 单独）与卵巢癌有关。具体而言，我们提出以下目标：1）评估 月经初潮早期对卵巢癌风险的影响是由一生中的高排卵次数介导的， 2)评估易感基因与终生排卵周期之间的基因-环境相互作用， 导致卵巢癌，3）阐明排卵在卵巢癌病因中的作用， 由于乳腺癌和/或卵巢癌家族史而处于高风险的女性队列。这将是第一个研究 利用基因组学方法评价基因与环境的相互作用。拟议的培训计划利用我的流行病学 通过增加癌症实质性知识和基因组数据分析技能进行培训， 以解决提出的目标和未来的研究在卵巢癌的遗传基础。执行 这些特定的目标将推进国家癌症研究所的使命，即了解遗传突变在组合中的作用 与生活方式和环境因素有关，在这里，在一个致命的，未被研究的癌症。

PROJECT SUMMARY/ABSTRACT Over 22,000 new cases of ovarian cancer are diagnosed in the United States each year, of whom only 47.6% survive beyond five years. Ovarian is the most fatal of the gynecologic cancers, due to there being few modifiable risk factors, no effective screening tool, a lack of specific symptoms, and a high probability of recurrence. The only preventive guideline for ovarian cancer is for high-risk, pre-menopausal women (BRCA1/2 carriers, or women with a family history of breast and/or ovarian cancer) to consider undergoing a risk-reducing bilateral salpingo-oopherectomy after child bearing is complete. No official guidelines exist for average-risk women. The etiology of the disease is poorly understood, yet, epidemiologic studies have consistently found that events which interrupt ovulation are protective against ovarian cancer risk, leading to the widely known “incessant ovulation” theory. Specifically, parity (higher number of live births), use of oral contraceptives, and lactation are protective against ovarian cancer, while early age at menarche, late age at menopause, infertility, and nulliparity have the opposite effect. However, the mechanisms through which the initiation and frequency of ovulation influence cancer risk are unknown. One possibility is that the chance of acquiring a cancer-causing mutation increases with each ovulatory cycle, due to inflammation during ovulation that alters the microenvironment to promote DNA damage and seeding of cancer cells. Using two well- characterized, large cohorts with deep phenotype, clinical, and genetic data (the United Kingdom Biobank and Breast Cancer Family Registry), we will use a novel lifecourse epidemiologic approach to investigate how an early life event (age at menarche) and long-term exposure (lifetime ovulatory cycles (LOC), a summary measure that may better capture the accumulated exposure to ovulations than reproductive events considered in isolation) relate to ovarian cancer. Specifically, we propose the following aims: 1) to assess whether the effect of early age at menarche on risk of ovarian cancer is mediated by a high lifetime number of ovulations, 2) to evaluate gene-environment interaction between susceptibility genes and lifetime ovulatory cycles in causing ovarian cancer, and 3) to elucidate the role of ovulations in ovarian cancer causation in a special cohort of women at high risk due to a family history of breast and/or ovarian cancer. This will be the first study to evaluate gene-environment interaction using LOC. The proposed training plan leverages my epidemiologic training by adding cancer substantive knowledge and genomic data analysis skills such that I will be equipped to address both the proposed aims and future research in the genetic bases of ovarian cancer. Execution of these specific aims will advance the NCI's mission to understand the role of inherited mutations in combination with lifestyle and environmental factors, here, in a lethal, understudied cancer.