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，并且其发病率正在增加。 拟议的分子流行病学研究超越了体重指数（BMI），以确定ccRCC患者 在考虑基于基因表达的分子肿瘤亚型时， 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， 对癌症患者的建议进行加权并完善预后因素。之间的反向关联 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，因为不清楚如何解释它。 肥胖悖论仍然在很大程度上未被探索。在拟议的研究中，我们将得出新的身体成分， 来自现有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 来自1200名非转移性ccRCC患者的存档肿瘤标本，这些患者在 Memorial Sloan Kettering Cancer Center，1995 - 2017年，随访临床结局。基于 我们假设肥胖悖论受到疾病异质性的影响， 特定的身体组成特征，包括低骨骼肌和内脏脂肪组织放射密度。在 目标1我们将研究身体成分变量（即，骨骼肌和脂肪的面积和密度 组织）与BMI相关，并与经验证的ccRCC分子肿瘤亚型相关， 与预后有关。在目标2中，我们将确定身体组成的哪些方面是独立的， 与肿瘤分子亚型后的生存率相关。通过探索肿瘤RNA表达 免疫、炎症、血管生成和其他癌症相关基因的表达因身体成分而异， 在目标3中，我们不仅将进一步了解身体大小与生物学之间的联系， 过程，但也可以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率领域的潜在影响， 肥胖悖论的临床解释，确定新的预后因素来自现成的 CT扫描，并为未来的行为或药理学干预措施的发展提供信息， 改善不断增长的ccRCC患者人群的临床结局。

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.