Presentation Authors: Alejandro Sanchez*, Fengshen Kuo, Stacey Petruzella, Oguz Akin, New York, NY, Michael Paris, Waterloo, Canada, Paul Russo, Timothy Chan, New York, NY, Marina Mourtzakis, Waterloo, Canada, Ari Hakimi, Helena Furberg, New York, NY
Introduction: Sarcopenia (low skeletal muscle mass) is independently associated with poor outcomes among patients with clear cell renal cell carcinoma (ccRCC). We examined gene expression differences among sarcopenic and non-sarcopenic patients to identify pathways that may explain this association.
Methods: 62 ccRCC patients treated by nephrectomy at Memorial Sloan Kettering Cancer Center were transcriptomically-profiled in The Cancer Genome Atlas. Computed tomography scans without contrast performed within 2 months of surgery were reviewed to determine skeletal muscle cross-sectional area. Sarcopenia (yes/no) was defined according to gender-specific international consensus definitions (skeletal muscle index of < 55 cm2/m2 for men and < 39 cm2/m2 for women). Baseline differences in clinicopathologic features were assessed using the Chi-squared test for categorical and t-test for continuous variables. Differential expression analyses were performed using the R package &[Prime]DESeq2&[Prime] (version 1.16.1). Gene set enrichment analyses (GSEA) were used to evaluate differences in Molecular Signatures Database hallmark gene sets (v6.0). Immune deconvolution using single-sample GSEA was utilized with previously published immune cell signatures (Bindea, et al.) to estimate immune cell infiltration. P-values were corrected for multiple testing (P-adjust) using the Benjamini-Hochberg method.
Results: The cohort was predominantly male (82%) and white (97%) and had localized disease (58%). Median age was 58.9 years (SD: 12.1). Overall, 47% were sarcopenic and these patients tended to be older (P < 0.001), to be obese (P < 0.001), and to present with higher AJCC stage (P=0.006). In primary tumor specimens, sarcopenic patients demonstrated increased expression of angiogenic, inflammatory (eg, 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 sarcopenic ccRCC patients harbor gene expression programs associated with more aggressive biology. Preliminary immune deconvolution analyses suggest that these patients have increased macrophage infiltration and decreased Th17 immune cell infiltration, both of which have been 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 of immune deconvolution results using immunofluorescence is necessary.
Source of Funding: Ruth L. Kirschstein Research Service Award T32CA082088 (AS).