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

摘要 透明细胞肾细胞癌（ccRCC）是最致命的泌尿系统恶性肿瘤，其发病率正在增加。 拟议的分子流行病学研究超越体重指数 (BMI) 来识别 ccRCC 患者 在根据基因表达考虑分子肿瘤亚型时存在预后不良的风险，并且直接 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，以最终提供信息 体重建议并完善癌症患者的预后因素。之间的逆关联 在 ccRCC 患者中持续观察到的 BMI 和死亡率提出了重大的临床挑战 对于患者、临床医生和研究人员来说，因为尚不清楚如何解释它。其背后的机制 肥胖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 来自现有的术前计算机断层扫描 (CT) 扫描的变量，并以转录组学方式表征 存档的肿瘤标本来自 1200 名非转移性 ccRCC 患者，这些患者在 1995 年至 2017 年间在纪念斯隆凯特琳癌症中心进行临床结果跟踪。基于 强有力的初步数据我们假设肥胖悖论受到疾病异质性的影响，并且 特定的身体成分特征，包括低骨骼肌和内脏脂肪组织放射密度。在 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）如何变化 组织）与 BMI 和经过验证的 ccRCC 分子肿瘤亚型相关，这些亚型具有很强的相关性 与预后相关。在目标 2 中，我们将确定身体成分的哪些方面是独立的 考虑分子肿瘤亚型后与生存相关。通过探索肿瘤RNA表达如何 免疫、炎症、血管生成和其他癌症相关基因的数量因身体成分和 在目标 3 的生存中，我们不仅会进一步了解体型与生物之间的联系 过程，但也可能确定三级预防研究的新目标。拟议的研究具有 通过澄清癌症流行病学和生存领域的潜力 肥胖悖论的临床解释，识别源自现成的新预后因素 CT 扫描，并为未来行为或药物干预措施的发展提供信息，旨在 改善不断增长的 ccRCC 患者的临床结果。

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.