Characteristics of tubal ligation and risk of epithelial ovarian cancer

描述（由申请人提供）：摘要尽管在输卵管结扎和上皮性卵巢癌风险之间观察到了强的负相关，但尚不清楚输卵管结扎的保护作用持续多久，或者这种负相关是否在特定的女性亚组中更强或仅在特定的女性亚组中观察到。此外，负责该程序的保护作用的潜在生物学机制尚不清楚。因此，在本申请中，我们将对输卵管结扎术与卵巢癌的风险进行详细的评估。在这项研究中，我们建议重新检查输卵管结扎术作为上皮性卵巢癌的一个重要危险因素，特别是评估手术相关和其他生活方式选择（例如，口服避孕药使用、生殖器滑石粉使用和卵巢癌个体风险）以及肿瘤特征。此外，我们计划评估输卵管结扎的癌症保护作用是否是通过炎症过程或MUC 1相关免疫介导的。使用前瞻性收集的问卷调查数据和石蜡包埋的卵巢肿瘤组织已经收集的妇女在护士健康研究（NHS）和NHSII，两个大的前瞻性队列研究开始于1976年（n= 121，700）和1989年（n= 116，430），分别，我们建议调查输卵管结扎的作用和潜在的重要机制的细节。在随访过程中（1976-2010年在NHS和1989-2009年在NHS II），我们预计将累积1,215例上皮性卵巢癌确诊病例，其中506例将有肿瘤组织可用。通过这两个队列的独特和前瞻性收集的资源，我们将确定与卵巢癌风险相关的输卵管结扎术最受益的人群，并阐明手术可能最具保护性的时间-这可能导致短期内可能制定的预防建议的重要变化。此外，我们将检查输卵管结扎的逆相关性是否因组织学亚型、假定的起源细胞（例如，对于来自远端输卵管而不是卵巢表面上皮的肿瘤），或肿瘤中炎性标志物的表达（磷酸化STAT 3（pSTAT 3）、pSTAT 5、考克斯-2、MUC 1）。考虑到输卵管结扎术降低这种疾病风险的证据的重要性，必须了解为什么以及如何这种手术提供保护，以及手术，女性或肿瘤的特征是否影响输卵管结扎术的有效性。如果这些问题得到解决，对改善关于输卵管结扎的卵巢癌预防建议有潜在的意义。此外，研究这种常见手术的保护作用的生物学机制将有望导致其他可能比输卵管结扎更具侵入性的预防途径。 公共卫生相关性：输卵管结扎术降低了上皮性卵巢癌的风险，在本申请中，我们将研究为什么以及如何这种程序提供保护，以及手术，女性或肿瘤的特征是否影响输卵管结扎术的有效性。这可以用来改善对这种疾病高风险妇女的预防建议。

DESCRIPTION (provided by applicant): ABSTRACT Although a strong inverse association has been observed between tubal ligation and epithelial ovarian cancer risk, it is unclear how long the protection from a tubal ligation lasts, or whether the inverse association is stronger for, or observed only in, specific subgroups of women. Further, the underlying biological mechanisms responsible for the protective effects of this procedure are unclear. Therefore, in this application, we will conduct a detailed evaluation of tubal ligation with ovarian cancer risk. In this study, we propose to re-examine tubal ligation as an important risk factor for epithelial ovarian cancer, and specifically, to evaluate a modifying role of both surgery-related and other lifestyle choices (e.g., oral contraceptive use, genital talc use, and individual risk of ovarian cancer) as well as tumor characteristics. In addition, we plan to assess whether the cancer protective effects of tubal ligation are mediated via inflammatory processes or MUC1-associated immunity. Using prospectively collected questionnaire data and paraffin-embedded ovarian tumor tissue already collected from women in the Nurses' Health Study (NHS) and NHSII, two large prospective cohort studies initiated in 1976 (n=121,700) and 1989 (n=116,430), respectively, we propose to investigate a role of tubal ligation and potentially important mechanisms in detail. Over the course of follow-up (1976-2010 in NHS and 1989-2009 in NHS II) we expect to accrue 1,215 confirmed cases of epithelial ovarian cancer, of which 506 will have tumor tissue available. With the unique and prospectively-collected resources of these two cohorts, we will identify populations who can most benefit from tubal ligation in relation to ovarian cancer risk as well as elucidate the timing of when the surgery may be most protective - this could lead to important changes in prevention recommendations that could be instituted in the short term. In addition we will examine whether the inverse association of tubal ligation varies by histologic subtype, putative cell of origin (e.g., for tumors derived from the distal fallopian tube rather than the ovarian surface epithelium), or expression of inflammatory markers in the tumor (phosphorylated STAT3 (pSTAT3), pSTAT5, COX-2, MUC1). Given the weight of evidence that tubal ligation reduces risk of this disease, it is imperative to understand why and how this procedure confers protection, as well as whether characteristics of the surgery, woman, or tumor impact the effectiveness of tubal ligation. If these questions are addressed, there are potential implications for improving ovarian cancer prevention recommendations regarding tubal ligation. Further, examining the biological mechanisms underlying the protective effect of this common procedure will hopefully lead to other avenues of prevention that may be less invasive than having a tubal ligation. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Tubal ligation reduces risk of epithelial ovarian cancer, in this application we will examine why and how this procedure confers protection, as well as whether characteristics of the surgery, woman, or tumor impact the effectiveness of tubal ligation. This can be used to improve prevention recommendations for women at high risk of this disease.