Abstract 3390: Impact of genomic alterations in <i>HMGB1</i>, <i>ROS1</i>, <i>IL6</i>, <i>FGFR1</i>, <i>FGFR2</i>, and <i>TLR4</i> on long-term survival outcomes in esophageal squamous cell carcinoma (ESCC)

Abstract Background. To test the hypothesis that the genomic alterations of HMGB1, ROS1, IL6, FGFR1, FGFR2, and TLR4 would be associated with long-term outcomes in patients with ESCC through disrupting normal immune surveillance and promote mechanisms that allow tumor cells to evade immune detection and destruction. These genes were also variously involved in the RTK-Ras pathway (ROS1, FGFR1, FGFR2), PI3K-Akt signaling (FGFR1, FGFR2, IL6 and TLR4), TLR signaling (TLR4 and IL6) and the SHP2 signaling (FGFR2 and IL6). Methods. This study merged five datasets and sorted out pure squamous cell carcinoma for analysis. GSE53624 was used for gene expression correlating to survival analysis on the genes of interest. Disease-free survival (DFS) and overall survival (OS) were calculated in patients whose survival times were available for Kaplan-Meier analysis. The log-rank test was used for comparison. Only patients with available survival data were put into the survival modes. Hazard ratios (HR) with 95% confidence interval (CI) were derived from the log-rank test. The research was conducted via the KEGG.jp, cBioPortal (accessed November 2024), and ESCCdb/Sichuan. Results. A total of 437 patients with 437 samples were selected. Male accounted for 78.5%. The altered and unaltered group comprises 66 (15%) and 371 (85%) patients. The top 10 mutated genes in this cohort are TP53, TTN, KMT2D, MUC16, CSMD3, PKHD1L1, ZNF804B, SYNE1, NOTCH1 and PCLO. Patients were assigned to either altered group (any alteration in the six genes of interest) or unaltered group. Compared with the unaltered group, the altered group has a higher nonsynonymous tumor mutational burden (TMB) [(median (IQR), 3.37 (2.07-5.23) vs 5.33 (4.32-6.3), p = 5.22e-8 by Wilcoxon test)] and higher mutation count [(median (IQR), 56 (13-117) vs 158.5 (125-187), p &amp;lt; 10e-10)]. DFS can be calculated in 76 patients. The altered group has a nonsignificant worse DFS with an HR of 1.171 (95% CI, 0.512-2.681). With more than 85 months of follow-up in 288 patients, compared with the altered group, the altered group shows significantly worse overall survival: median and 95% CI, 40.93 mo. (28.42 mo. - not reached) vs. 18.63 mo. (18.17 mo. - 28.13 mo.), HR = 2.16 (1.33 - 3.52)]. Gene expression versus survival analyses revealed that higher HMGB1 expression harbors a significantly worse prognosis (p &amp;lt; 0.008). Conclusions. These in silico and dataset experiments leveraging the genomic data from ESCC demonstrate that despite having a higher mutation count and TMB, which might elicit more tumor neoantigens for immune recognition and eradication, the altered group with genomic alterations in any of the six genes might still have a significantly worse long-term survival prognosis. The novelty of the study findings needs further investigation. Citation Format: Victor C. Kok. Impact of genomic alterations in HMGB1, ROS1, IL6, FGFR1, FGFR2, and TLR4 on long-term survival outcomes in esophageal squamous cell carcinoma (ESCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3390.