Molecular Pathoepidemiology of Endometrial Cancer Risk

描述（由申请人提供）：子宫内膜癌是发达国家最常见的妇科恶性肿瘤，也是美国女性第四常见的癌症。尽管存活率很高，但早期子宫内膜癌的幸存者在诊断和治疗多年后，与健康对照组相比，生活质量仍然较低。生活方式因素与I型子宫内膜癌的病因密切相关，肥胖可能占高收入社会子宫内膜癌发病率的三分之一以上。虽然许多可改变的危险因素是公认的，但子宫内膜癌发生背后的机制仍不清楚。子宫内膜癌被认为是激素致癌的一种模型，因为绝经后雌激素的使用没有孕激素的对抗，肥胖是最确定的风险因素。最近的研究结果表明，除了性类固醇途径，改变激素水平的能量平衡途径可能在疾病的发病机制中发挥重要作用。重要的细节，如每种途径介导主要风险因素对疾病的影响的程度以及参与这些过程的特定生物标志物尚未阐明。为此，在这一竞争性更新中，我们建议了解子宫内膜癌的几个已建立和新的（即胰岛素指数）风险因素的分子基础，重点是性类固醇和能量平衡途径的作用。通过评估性类固醇和能量平衡相关标志物在肿瘤组织（和匹配的相邻非肿瘤组织）中的表达与生殖和生活方式暴露的关系，我们将对这些途径中的每一个的重要性提供相当多的见解。最后，由于子宫内膜癌的几个可改变的和相对较强的环境和生活方式的危险因素是众所周知的，子宫内膜癌是一个特别适合的癌症，其中检查环境，生殖系遗传学和体细胞遗传学的相互作用。在我们长达36年的随访研究中，我们预计将有722例I型子宫内膜癌病例的肿瘤组织可供分析。一项大型前瞻性队列研究是阐明子宫内膜癌发病机制的生物学机制和确定不同病因亚型存在的有力方法。这项建议的一个主要优势是，它将通过为我们提供受既定和新的子宫内膜癌危险因素影响的体细胞分子变化的数据，增强我们目前对子宫内膜癌易感性背后的机制的理解。这些发现将完善子宫内膜癌风险预测，为确定最高风险的妇女奠定基础，这些妇女将最受益于定制和具有成本效益的生活方式和/或化学预防干预策略。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Despite high survival rates, survivors of early stage endometrial cancer continue to experience a lower quality of life many years after diagnosis and treatment compared to healthy controls. Lifestyle factors are strongly implicated in the etiology of Type I endometrial cancer and obesity may account for over one-third of incident endometrial cancer in high-income societies. Although a number of modifiable risk factors are well-established, the mechanisms behind endometrial carcinogenesis remain unclear. Endometrial cancer is considered a model of hormonal carcinogenesis as use of postmenopausal estrogen unopposed by progesterone, and obesity are the best-established risk factors. Recent findings suggest that in addition to the sex steroid pathway, altered hormone levels in energy balance pathways may play a substantial role in disease pathogenesis. Important details such as the degree to which each pathway mediates the effects of major risk factors on disease and the specific biomarkers involved in these processes have not been elucidated. To this end, in this competing renewal we propose to understand the molecular basis for several established and novel (i.e. insulin index) risk factors of endometrial cancer, with a focus on the roles of the sex steroid and energy balance pathways. By evaluating the expression of sex steroid and energy balance related markers in tumor tissue (and matched adjacent non-tumor tissue) in relation to reproductive and lifestyle exposures, we will provide considerable insight into the importance of each of these pathways. Finally, because several modifiable and relatively strong environmental and lifestyle risk factors for endometrial cancer are well-established, endometrial cancer is a particularly suitable cancer in which to examine the interplay of environment, germline genetics, and somatic genetics. In our study with up to 36 years of follow-up, we expect to have 722 Type I endometrial cancer cases with tumor tissue available for analysis. A large prospective cohort study is a powerful approach to elucidate the biological mechanisms involved in endometrial cancer pathogenesis and identify the existence of distinct etiological subtypes. A major strength of this proposal is that it will enhance our current mechanistic understanding behind endometrial cancer susceptibility by providing us with data on somatic molecular changes influenced by established and novel endometrial cancer risk factors. Such findings would refine endometrial cancer risk prediction, creating a basis for identifying women at highest risk that would most benefit from tailored and cost-effective lifestyle and/or chemopreventive intervention strategies.