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.
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