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

项目摘要/摘要 美国每年新诊断的卵巢癌病例超过2.2万例，其中只有47.6% 寿命超过五年。卵巢癌是妇科癌症中最致命的，因为卵巢癌很少。 可修改的风险因素，没有有效的筛查工具，缺乏特定症状，以及 复发。卵巢癌的唯一预防指南是针对绝经前的高危女性。 (BRCA1/2携带者或有乳腺癌和/或卵巢癌家族史的妇女)考虑接受 分娩完成后降低风险的双侧输卵管卵巢切除术。目前还没有官方的指导方针 中等风险的女性。这种疾病的病因尚不清楚，然而，流行病学研究已经 一致发现，中断排卵的事件对卵巢癌风险具有保护作用，导致 广为人知的“持续排卵”理论。具体地说，产次(较高的活产数)，使用口服 避孕和哺乳可以预防卵巢癌，而月经初潮时的早龄段，月经初潮的晚龄段 更年期、不孕症和不孕会产生相反的影响。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，每个排卵周期中获得致癌突变的人数都会增加。 这改变了微环境，促进了DNA损伤和癌细胞的播种。用两口井- 具有深入的表型、临床和遗传数据的特征、大群组(英国生物库和 乳腺癌家庭登记)，我们将使用一种新的生命过程流行病学方法来调查 早期生活事件(月经初潮年龄)和长期暴露(终生排卵周期(LOC)，综述 比考虑的生殖事件更好地捕捉累积的排卵暴露的衡量标准 孤立地)与卵巢癌有关。具体地说，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通过一生中高排卵数来调节的， 2)评估易感基因与终生排卵周期之间的基因-环境交互作用 3)阐明排卵在卵巢癌病因中的作用。 有乳腺癌和/或卵巢癌家族史的高危妇女队列。这将是第一次研究 用LOC评价基因与环境的交互作用。拟议的培训计划充分利用了我的流行病学 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，这样我就可以 以解决建议的目标和未来卵巢癌遗传学基础的研究。签立 这些具体目标将推动NCI了解遗传突变在组合中的作用的使命 生活方式和环境因素，在这里，在一种致命的，未被研究的癌症中。

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.