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

摘要 肥胖，按BMI(体重/身高2)分类，与至少12种癌症的高风险有关 绝经后的女性。然而，体重指数是理解身体成分病因学的一个特别生硬的工具。 对癌症风险的贡献，并实际确定干预和癌症预防的因果目标。这是 因为BMI没有解决肥胖-癌症关联的核心假说-那么高 腹部内脏脂肪组织(VAT)水平，绝经后在更大程度上积累在 腹腔内，通过其在炎症、 代谢和免疫功能障碍--癌症的特征。而皮肤下的脂肪组织 (皮下，SAT)甚至可能是良性的。BMI也不能区分脂肪和肌肉(即柔软的瘦肉 组织，LST)，它有可能改善这些增值税驱动途径的功能障碍。不过， 肌肉尚未被研究与肿瘤发生有关，尽管它正在成为一个重要的组成部分。 生存之道。尽管与肥胖相关的癌症增加，而且三角测量的研究正在兴起，以告知 致癌增值税假说，该假说实际上是未经检验的。这项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来检查两具详细的身体 成分和人体同时暴露与癌症发病率和死亡率的关系。这 反映与测量特定数据相关的历史高成本、可用性和辐射暴露 腹部脂肪组织的CT和MRI检查。双能X射线吸收法的最新进展 (DXA)技术，通过CT和MRI验证，使我们能够量化腹部VAT和SAT 现有的DXA扫描是在特征明确的妇女健康倡议(WHI)范围内进行的。我们将以同样的方式衡量 腹部LST，以补充这一近11,000人的预期队列中可用的全身测量 女性在基线和3年、6年和9年后进行重复的DXA测量。我们将研究这些水平如何 腹部VAT、SAT和LST，以及总体身体成分和人体测量，与肥胖有关- 相关的癌症发病率和死亡率。此外，我们将在 与肺癌的关系(不被归类为肥胖相关)，以解决文献中的异常情况，即BMI (反向)和腰部(正)与肺癌相关。我们假设增值税，在其他情况下 对于所有癌症来说，组织都是一个危险因素。这一完全独一无二的数据集将在25年内确定结果 对上述腹部脂肪组织储存库和LST的病因作用提供新的见解 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。这项研究将提供信息并改变临床实践，超出预期的影响 我们目标的结果预示着。总而言之，我们将解决临床和临床两方面的主要知识差距

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