Prognostic Significance of <i>SOX9</i> and Its Combination With <i>RAS</i> and <i>TP53</i> Mutations Following Colorectal Cancer Liver Metastasectomy

Previous studies have highlighted the significance of genetic mutations in predicting the prognosis of patients undergoing resection for colorectal liver metastases (CRLM). Nonetheless, most studies were based on small-panel gene detection. The present study aimed to identify gene mutations associated with prognosis in CRLM patients using high-throughput sequencing. Next-generation sequencing of 1021 genes was performed on 283 CRC patients, and gene mutations associated with overall survival (OS) were identified using Cox models and validated in external cohorts. Moreover, the relationship between SOX9 mutation and its expression was investigated. Next, the pro-tumorigenic role of SOX9 was confirmed using lentiviral shRNA-mediated SOX9 knockdown and performing in vitro and in vivo functional studies. CRLM patients with SOX9 mutations had a significantly worse prognosis than those with wild-type status. Multivariable analysis identified SOX9, RAS, and TP53 mutations as significant independent prognostic factors. Importantly, the combination of these three mutations correlated with a worse prognosis than any one or two mutations. Furthermore, these findings were validated in the BJCH (N = 176) and MSKCC (N = 321) cohorts. SOX9 mutations were associated with increased expression, and silencing SOX9 reduced CRC proliferation and migration. Overall, our study suggests that SOX9 may serve as a potential therapeutic target and that a model incorporating RAS, TP53, and SOX9 mutations could more accurately predict outcomes in patients with CRLM.