PROGNOSTIC VALUE OF IFNγ-ASSOCIATED GENES SIGNATURE IN LUNG SQUAMOUS CELL CARCINOMA: TCGA-BASED ANALYSIS

Lung squamous cell carcinoma (LUSC) represents the second most prevalent histological subtype of non-small cell lung cancer and is characterized by a high level of genomic instability, elevated mutational burden, and marked immune infiltration. These features underscore the potential of immunotherapy in this context; however, clinical responses remain heterogeneous. One of the promising molecular biomarkers of immune activation is the IFNγ-associated gene signature, which comprises the expression of ten transcriptomic markers involved in the interferon-gamma (IFNγ) signaling cascade: IDO1, IRF9, CCR5, STAT1, CXCL9, CXCL10, CXCL11, PRF1, IFNG, and HLA-DRA. The objective of this study was to evaluate the association between the expression level of the IFNγ gene signature and clinicopathological as well as molecular characteristics in patients with squamous cell carcinoma of the lung, using open-access data from the TCGA-LUSC cohort. The analysis included 419 patients with complete clinical, pathological, transcriptomic, survival, and mutation data (TP53, TTN, PIK3CA, KEAP1/NFE2L2). The IFNγ signature score was calculated as the mean log₂(RSEM+1) of ten genes. ROC analysis set a threshold at 7.32, stratifying patients into low (n=196) and high (n=223) expression groups. Statistical analysis in Stata 19.5 included χ² tests for categorical variables, Spearman’s correlation (visualized as a heatmap), Kaplan–Meier survival curves with log-rank testing, and multivariate Cox regression (HRs, 95 % CIs, p-values). Significance was set at p<0.05. Correlation analysis revealed a high degree of concordance in expression across most genes within the signature, particularly for IDO1 (ρ=0.74), as well as CXCL9, CXCL10, and CXCL11 (all ρ≈0.40), suggesting common transcriptional regulation mechanisms. In the demographic analysis, the mean age was 67.0±8.53 years, with no significant differences between expression groups (p=0.930); similarly, sex (p=0.750) and disease stage (p=0.503) were not associated with the level of IFNγ signature expression. Mutation analysis indicated that TTN, TP53, and PIK3CA mutations were not significantly associated with IFNγ signature expression levels (p>0.05); however, KEAP1/NFE2L2 mutations were more frequently observed in patients with high expression of the signature (35.9 % vs. 18.9 %, p<0.0001). Kaplan–Meier analysis showed a median overall survival of 55.2 months in the high-expression group versus 44.8 months in the low-expression group; however, the log-rank test did not reveal a statistically significant difference (χ²(1)=0.37, p=0.5453). In the Cox regression model, the IFNγ signature was not independently associated with survival (HR=0.94; 95 % CI: 0.70–1.28; p=0.711), unlike TP53 (HR=0.53; p=0.009) and TTN mutations (HR=0.58; p=0.005), which were associated with reduced mortality risk. In conclusion, the results demonstrate a high transcriptional concordance among genes within the IFNγ signature and its association with certain molecular characteristics; however, the signature does not appear to possess independent prognostic value in patients with lung squamous cell carcinoma.