Adipose and Lean Soft Tissue Depots, Cancer Risk and Mortality in Postmenopausal Women

摘要 根据BMI（体重/身高2）分类的肥胖与至少12种癌症的高风险相关， 绝经后妇女。然而，体重指数是一个特别钝的工具，以了解身体组成的病因 癌症风险的贡献，并实际确定干预和癌症预防的因果目标。这是 因为BMI并没有解决肥胖与癌症相关性的核心假设--高BMI 腹部内脏脂肪组织（VAT）水平，在绝经后更大程度上积累， 腹腔内，通过其在炎症， 代谢和免疫功能紊乱-癌症的标志。而皮下的脂肪组织 （皮下，SAT）甚至可能是良性的。BMI也不区分脂肪和肌肉（即瘦软 组织，LST），其具有改善这些VAT驱动途径中的功能障碍的潜力。然而，尽管如此， 肌肉与肿瘤发生的关系尚未得到研究，尽管它正在成为一个重要的组成部分 生存。尽管肥胖相关癌症的增加和新兴的研究三角形，以告知 致癌增值税假说，该假说是有效的未经检验。这一建议具有特别重要的意义 因为证据基础缺乏足够有力的研究，能够检查详细的身体 在癌症发病率和死亡率方面，这 反映了历史上与测量特定辐射相关的高昂成本、可用性和辐射暴露。 通过CT和MRI检查腹部脂肪组织。双能X射线吸收法的最新进展 (DXA)通过CT和MRI验证的技术，使我们能够量化腹部VAT和SAT， 现有的DXA扫描在良好的特点妇女健康倡议（WHI）。我们将以类似的方式测量 腹部LST，以补充全身测量可用，在这个前瞻性队列近11，000 在基线和3年、6年和9年后重复DXA测量的女性。我们将研究 腹部增值税，SAT和LST，以及全身组成和人体测量，与肥胖有关- 相关的癌症发病率和死亡率。此外，我们将在 与肺癌相关（未归类为肥胖相关），以解决文献中的异常，即BMI （反向）和腰部（正）与肺癌的关系。我们假设，增值税，在其他的背景下， 是所有癌症的危险因素。这一具有25年裁定结果的完全独特的数据集将 为上述腹部脂肪组织库和LST的病因学作用提供了新的见解 癌症风险和癌症死亡率。我们将使用全面、严格的分析方法来解决我们的 目标和假设。该研究将告知并改变临床实践，超出预期影响， 我们的目标的结果预示着。总之，我们将解决临床和

ABSTRACT Obesity, classified by BMI (body weight/height2) is associated with higher risk of at least 12 cancers in postmenopausal women. Yet, BMI is a particularly blunt tool to understand the etiology of body composition contributions to cancer risk, and actually identify causal targets for intervention and cancer prevention. This is because BMI does not address the central hypothesis underlying the obesity-cancer association- that higher levels of abdominal visceral adipose tissue (VAT), which accumulates to a greater extent post menopause in the intra-abdominal cavity, drives the pathophysiology of obesity-related cancers via its role in inflammatory, metabolic, and immune dysfunction - hallmarks of cancer. Whereas adipose tissue just under the skin (subcutaneous, SAT) may even be benign. BMI also does not delineate between fat and muscle (i.e. lean soft tissue, LST), which has the potential to ameliorate dysfunction in these VAT driven pathways. Nevertheless, muscle has not been examined in relation to tumorigenesis, though it is emerging as an important component of survival. Despite the increase in obesity-related cancers and burgeoning research triangulated to inform the carcinogenic VAT hypothesis, the hypothesis is effectively untested. This proposal is of particular significance because the evidence base lacks sufficiently powered studies that are able to examine both detailed body composition and anthropometric exposures simultaneously in relation to cancer incidence and mortality. This reflects the historical prohibitive cost, availability, and radiation exposure associated with measuring specific abdominal adipose tissue depots by CT and MRI. Recent advances in Dual Energy X-Ray Absorptiometry (DXA) technology, validated against CT and MRI, have allowed us to quantify abdominal VAT and SAT from existing DXA scans within the well-characterized Women's Health Initiative (WHI). We will similarly measure abdominal LST, to complement the total body measures available, in this prospective cohort of nearly 11,000 women with repeated DXA measurements at baseline and 3, 6 and 9 years later. We will examine how levels of abdominal VAT, SAT and LST, as well as total body composition and anthropometry, associate with obesity- related cancer incidence and mortality. Moreover, we will examine these body composition measures in relation to lung cancer, (not classified as obesity-related) to address anomalies in the literature, i.e. BMI (inverse) and waist (positive) associations with lung cancer. We hypothesize that VAT, in the context of other tissues, is a risk factor, for all cancers. This wholly unique dataset with adjudicated outcomes over 25 years will provide novel insight into the etiological role of the aforementioned abdominal adipose tissue depots and LST in cancer risk and cancer mortality. We will use a comprehensive, rigorous analytic approach to address our aims and hypotheses. The study will inform and alter clinical practice beyond the anticipated impact that the results from our aims portend. In sum, we will address a major knowledge gap of both clinical and