Characteristics of tubal ligation and risk of epithelial ovarian cancer

尽管已经观察到输卵管结扎与上皮性卵巢癌风险之间存在很强的负相关，但尚不清楚输卵管结扎的保护持续多长时间，或者这种负相关是否在特定的女性亚组中更强，或者仅在特定的女性亚组中观察到。此外，造成这一过程保护作用的潜在生物学机制尚不清楚。因此，在本应用中，我们将对输卵管结扎与卵巢癌风险进行详细评估。在这项研究中，我们建议重新检查输卵管结扎作为上皮性卵巢癌的重要危险因素，特别是评估手术相关和其他生活方式选择（例如口服避孕药的使用、生殖器滑石粉的使用和卵巢癌的个体风险）以及肿瘤特征的改变作用。此外，我们计划评估输卵管结扎的癌症保护作用是否通过炎症过程或muc1相关免疫介导。使用前瞻性收集的问卷数据和已经从护士健康研究（NHS）和NHSII中收集的石蜡包埋卵巢肿瘤组织，分别于1976年（n=121,700）和1989年（n=116,430）开始的两项大型前瞻性队列研究，我们建议详细调查输卵管结扎的作用和潜在的重要机制。在随访过程中（1976-2010年NHS和1989-2009年NHS II），我们预计将积累1215例上皮性卵巢癌确诊病例，其中506例将有肿瘤组织可用。利用这两个队列的独特和前瞻性收集的资源，我们将确定从输卵管结扎中获益最多的人群与卵巢癌风险有关，并阐明手术可能最具保护作用的时机-这可能导致在短期内制定的预防建议的重要变化。此外，我们将研究输卵管结扎的负相关是否因组织学亚型、推定的起源细胞（例如，肿瘤起源于远端输卵管而不是卵巢表面上皮）或肿瘤中炎症标志物（磷酸化STAT3 （pSTAT3）、pSTAT5、COX-2、MUC1）的表达而异。鉴于有大量证据表明输卵管结扎术降低了这种疾病的风险，因此有必要了解这种手术为何以及如何提供保护，以及手术、女性或肿瘤的特征是否会影响输卵管结扎术的有效性。如果这些问题得到解决，有潜在的影响，以改善卵巢癌预防建议有关输卵管结扎。此外，研究这种普通手术保护作用的生物学机制，有望找到比输卵管结扎侵入性更小的预防方法。

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.