Mechanisms underlying the association between sarcopenia and poor oncologic outcomes in clear cell renal cell carcinoma.

662 Background: Sarcopenia (low skeletal muscle mass) is associated with poor outcomes in patients with ccRCC. The mechanisms underlying this association are unclear. To understand this association, we examined gene expression differences by sarcopenic status in patients with ccRCC. Methods: The cohort consisted of 62 ccRCC patients treated by nephrectomy and previously transcriptomically-profiled in the Cancer Genome Atlas. Computed tomography scans without contrast performed within two months of surgery were reviewed to determine skeletal muscle cross-sectional area. Sarcopenia (yes/no) was defined according to gender-specific international consensus definitions. Baseline differences in clinicopathologic characteristics were assessed using the Chi-squared test for categorical and t-test for continuous variables. Differential expression analyses were performed using the R package “DESeq2.” Gene set enrichment analyses (GSEA) and single-set GSEA were used to evaluate differences in MSigDB Hallmark gene sets and estimate immune cell infiltration, respectively. P-values were corrected for multiple testing (p-adjust). Results: The cohort was predominantly male (82%), white (97%) and had localized disease (58%). Median age was 58.9 years (SD: 12.1). Sarcopenic (47%) patients were older (p < 0.001), obese (p < 0.001), and presented with higher AJCC stage (p = 0.006). In primary tumor specimens, sarcopenic patients demonstrated increased expression of angiogenic, inflammatory (e.g., IL-6, TNF-alpha), and epithelial mesenchymal transition programs (p-adjust < 0.05). Furthermore, sarcopenic patients had higher macrophage (p = 0.003) and Th17 immune cell infiltration (p = 0.003). Conclusions: Our findings suggest that ccRCC patients who are sarcopenic harbor gene expression programs associated with more aggressive biology. Increased macrophage infiltration and decreased Th17 immune cell infiltration have been previously associated with worse prognosis in ccRCC. It is not clear whether sarcopenia is a cause or consequence of tumor aggressiveness. Validation of these results in a larger cohort of patients and orthogonal validation are ongoing.