Body composition and the obesity paradox in clear cell renal cell carcinoma

摘要 肾透明细胞癌(CcRCC)是最致命的泌尿系恶性肿瘤，其发病率呈上升趋势。 拟议的分子流行病学研究超越了体重指数(BMI)来识别慢性肾细胞癌患者。 在考虑基于基因表达的分子肿瘤亚型时，有预后不良的风险，并且是直接的 对ASCO立场声明的回应，该声明呼吁进行更多与肥胖相关的研究，以最终为 为癌症患者推荐体重并提炼预后因素。两者之间的反向关联 在慢性肾细胞癌患者中持续观察到的体重指数和死亡率是一个重大的临床挑战。 对于患者、临床医生和研究人员来说，因为还不清楚如何解释它。潜在的机制 肥胖症悖论在很大程度上仍未得到探索。在拟议的研究中，我们将得出新的身体成分 来自现有的手术前计算机断层扫描(CT)的变量，以及转录-特征 1200例非转移性肾细胞癌患者行肾切除术后的存档肿瘤标本 纪念斯隆·凯特琳癌症中心在1995-2017年间，并跟踪临床结果。基于 强有力的初步数据，我们假设肥胖悖论是受疾病异质性和 特定的身体成分特征，包括低骨骼肌和内脏脂肪组织的放射密度。在……里面 目标1我们将检查身体成分变量(即骨骼肌和脂肪的面积和密度 组织)与BMI和有效的ccRCC分子肿瘤亚型相关 与预后相关。在目标2中，我们将确定身体组成的哪些方面是独立的 在考虑了分子肿瘤亚型后，与生存相关。通过探索肿瘤RNA的表达 免疫学、炎症性、血管生成和其他癌症相关基因的身体组成和 在目标3中生存，我们不仅将进一步了解身体大小和生物学之间的联系 但也可能为三级预防研究确定新的目标。拟议的研究具有 可能通过澄清癌症流行病学和生存领域的 肥胖症悖论的临床解释，从现成的数据中找出新的预后因素 CT扫描，并通知未来行为或药物干预的发展旨在 改善不断增长的慢性肾细胞癌患者的临床结局。

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is the most lethal urologic malignancy and its incidence is increasing. The proposed molecular epidemiology study moves beyond body mass index (BMI) to identify ccRCC patients at risk of poor prognosis while considering molecular tumor subtype based on gene expression, and is in direct response to an ASCO position statement that calls for more obesity-related research to ultimately inform weight recommendations and refine prognostic factors for cancer patients. The inverse association between BMI and mortality that is consistently observed among ccRCC patients presents a significant clinical challenge for patients, clinicians, and researchers because it is not clear how to interpret it. Mechanisms underlying the obesity paradox remain largely unexplored. In the proposed study, we will derive new body composition variables from existing, pre-surgical computed tomography (CT) scans, and transcriptomically-characterize the archived tumor specimens from 1200 non-metastatic ccRCC patients who were treated by nephrectomy at Memorial Sloan Kettering Cancer Center between 1995-2017 and followed for clinical outcomes. Based on strong preliminary data we hypothesize that the obesity paradox is influenced by disease heterogeneity and specific body composition features including low skeletal muscle and visceral adipose tissue radiodensity. In Aim 1 we will examine how body composition variables (i.e., area and density of skeletal muscle and adipose tissues) are associated with BMI and with validated ccRCC molecular tumor subtypes that are strongly associated with prognosis. In Aim 2 we will identify which aspects of body composition are independently associated with survival after accounting for molecular tumor subtype. By exploring how tumor RNA expression of immunologic, inflammatory, angiogenic and other cancer-related genes differ by body composition and survival in Aim 3, we will not only further our understanding of the link between body size and biological processes, but may also identify novel targets for tertiary prevention studies. The proposed research has the potential to make a lasting impact on the fields of cancer epidemiology and survivorship by clarifying the clinical interpretation of the obesity paradox, identifying novel prognostic factors derived from readily available CT scans, and informing the development of future behavioral or pharmacological interventions designed to improve clinical outcomes for the growing population of ccRCC patients.