Alterations in HMGB1, ROS1, FGFR1, FGFR2, IL6, and TLR4 are associated with worse survival in patients with esophageal squamous cell carcinoma

Introduction:
This study investigated the impact of alterations in six key genes (HMGB1, ROS1, IL6, FGFR1, FGFR2, and TLR4) on survival outcomes in patients with esophageal squamous cell carcinoma (ESCC). These genes are implicated in signaling pathways such as RTK-Ras, PI3K-Akt, TLR, and SHP2.

Material and methods:
Genomic data from five datasets were merged to identify 437 ESCC patients, categorized into altered (n = 66, 15%) and unaltered (n = 371, 85%) groups. Gene expression was analyzed using the GSE53624 dataset, and survival outcomes were assessed with Kaplan-Meier curves and log-rank tests. Hazard ratios (HR) were derived to quantify risk.

Results:
The altered group exhibited a significantly higher tumor mutational burden (TMB) and mutation count than the unaltered group (p < 1E-7). While disease-free survival analysis of 76 patients showed no significant difference, overall survival (OS) analysis of 288 patients demonstrated significantly worse survival in the altered group [median OS (95% CI): 18.63 months (18.17–28.13) vs. 40.93 months (28.42 – not reached); HR = 2.16 (1.33–3.52)]. Additionally, higher HMGB1 expression was significantly associated with poorer survival (p < 0.008). Expression-treatment response correlation using the GSE45670 dataset showed that HMGB1 expression in the pathological complete remission group was significantly higher than in the normal epithelium group, p = 0.016.

Conclusions:
This study highlights that genomic alterations in these six genes are associated with poorer OS in ESCC, despite higher TMB potentially increasing tumor neo-antigens. These findings underscore the need for further research to explore their prognostic and therapeutic potential.