Prognostic impacts of skeletal muscle gene expression and cachexia in advanced colorectal cancer

Background: Cancer cachexia is a complex metabolic syndrome characterized by severe muscle loss, reduced physical function, and diminished therapeutic response. Despite its clinical impacts, the transcriptional landscape of cachexia in patients with advanced peritoneal carcinomatosis from metastatic colorectal cancer (pmCRC) remains poorly defined. Our study aims to characterize alterations in skeletal muscle with associated cachexia in pmCRC patients. Methods: Muscle biopsies were obtained from 17 pmCRC patients consented for IRB tissue collection and undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), classified as myopenic (n=7) or non-myopenic (n=11) based on skeletal muscle index (SMI cm2/m2). Biopsies were sent for RNA sequencing and differential expression analysis was performed utilizing statistical algorithms within edgeR software. We compared the two cohorts and selected differentially expressed genes (DEGs) with significantly increased or decreased expression (>2-fold change and p-value <0.05). Enrichment analysis identified gene sets and pathways relevant to cachexia pathophysiology. Last, survival analysis was performed to assess the prognostic value of identified DEGs in predicting patient outcomes. Results: Our analysis revealed 231 genes DEGs, including 75 upregulated and 156 downregulated genes in the myopenic group. Enrichment analysis exhibited several pathways involved in immune cell signaling. Overall survival analysis revealed associations with survival outcomes for seven DEGs-six of which have associated prognostic value in colorectal cancer or other cancer variants including pancreatic adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma and oral squamous cell carcinoma. High expression of one DEG and low expression of the remaining prognostic genes were linked with poor survival in our patient cohort. Conclusions: Our study highlights molecular features of cancer-induced cachexia in pmCRC and several potential diagnostic and prognostic biomarkers.