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

透明细胞肾细胞癌的身体成分和肥胖悖论

• 批准号: 10228024
• 负责人: Anna Helena Furberg-Barnes
• 金额: $ 65.33万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228024
• 关键词: Accounting; Address; Adipose tissue; Affect; Age; American Society of Clinical Oncology; Archives; Area; Behavior Therapy; Behavioral; Biological; Biological Process; Body Composition; Body Size; Body Weight; Body mass index; Body measure procedure; Cancer Patient; Cancer Survivorship; Clear cell renal cell carcinoma; Clinical; Colorectal Cancer; Data; Development; Disease; Fatty acid glycerol esters; Future; Gene Chips; Gene Expression; Genes; Genetic Transcription; Guidelines; Immune; Immune system; Immunologics; Immunotherapy; Incidence; Inflammatory; Intervention; Intuition; Link; Longterm Follow-up; Malignant Neoplasms; Measurement; Mediating; Memorial Sloan-Kettering Cancer Center; Messenger RNA; Metabolic; Metabolic Diseases; Metastatic to; Modeling; Molecular; Molecular Epidemiology; Muscle; Nephrectomy; Nonmetastatic; Nutritional; Obesity; Obesity Epidemic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Population; Positioning Attribute; Prognosis; Prognostic Factor; Recommendation; Renal carcinoma; Research; Research Personnel; Risk; Risk Factors; Scanning; Skeletal Muscle; Smoking; Specimen; Time; Tissues; Tumor Markers; Tumor Subtype; Tumor-infiltrating immune cells; Up-Regulation; Visceral; Weight; X-Ray Computed Tomography; base; cancer epidemiology; clinically relevant; comorbidity; density; design; disease heterogeneity; energy balance; epidemiology study; high body mass index; improved; individual patient; insight; molecular scale; molecular subtypes; mortality; mortality risk; novel; novel strategies; patient population; patient subsets; predict clinical outcome; premature; prognostic model; response; risk prediction model; sex; strength training; subcutaneous; tertiary prevention; therapy design; transcriptomics; treatment response; treatment trial; tumor; urologic

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.

抽象的 透明细胞肾细胞癌（CCRCC）是最致命的泌尿科恶性肿瘤，其发病率正在增加。 拟议的分子流行病学研究超出了体重指数（BMI），以鉴定CCRCC患者 在基于基因表达的分子肿瘤亚型的同时，预后不良的风险，并且直接 对ASCO职位声明的回应，该声明要求进行更多与肥胖有关的研究以最终告知 体重建议和针对癌症患者的预后因素。逆关联 在CCRCC患者中始终观察到的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，因为尚不清楚如何解释它。基础的机制 肥胖悖论在很大程度上尚未探索。在拟议的研究中，我们将得出新的身体组成 来自现有的，外科计算机断层扫描（CT）扫描的变量，并以转录为特征使该变量化 来自1200名非转移性CCRCC患者的归档肿瘤标本，这些患者在 1995 - 2017年之间的纪念斯隆·克特林癌症中心，随后进行临床结果。基于 强大的初步数据我们假设肥胖悖论受疾病异质性和 特定的身体组成特征，包括低骨骼肌和内脏脂肪组织放射性。在 目标1我们将研究身体组成变量（即骨骼肌和脂肪的面积和密度） 组织）与BMI和经过验证的CCRCC分子肿瘤亚型有关 与预后有关。在目标2中，我们将确定身体成分的哪些方面是独立的 与分子肿瘤亚型有关后的生存相关。通过探索肿瘤RNA的表达方式 免疫，炎症，血管生成和其他与癌症相关的基因的不同因素因身体成分和 在AIM 3中的生存，我们不仅将进一步了解体型与生物学之间的联系 过程，但也可能识别出第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产生持久影响的潜力 肥胖悖论的临床解释，鉴定出可随时获得的新的预后因素 CT扫描，并告知未来行为或药理干预措施的发展 改善CCRCC患者不断增长的人群的临床结果。