POU2F3 expression in lung squamous cell carcinoma: transcriptomic and immunohistochemical profiling with prognosis

Lung squamous cell carcinoma (LUSC) lacks well-defined molecular targets. This study investigated the clinical and biological relevance of POU class 2 homeobox 3 (POU2F3), a tuft cell-associated transcription factor, in LUSC.

RNA sequencing data of patients with LUSC from The Cancer Genome Atlas (TCGA cohort, n = 190) was analysed and compared to a cohort of surgically resected cases analyzed via immunohistochemistry (IHC cohort, n = 137). Prognostic impact was assessed via survival analyses. Transcriptomic features, pathway enrichment, and immune profiles were evaluated via differentially expressed gene analysis, Gene Set Enrichment Analysis, and CIBERSORTx.

High POU2F3 expression independently predicted poor overall survival in the TCGA cohort (HR = 2.06, 95% CI: 1.04-4.08, P = 0.039). In contrast, POU2F3 expression was not prognostic in the IHC cohort (P = 0.995). Morphologically, POU2F3-positive tumours were enriched for non-keratinizing and poorly differentiated subtypes. Transcriptomic analysis showed suppression of proliferation and immune-related pathways (FDR < 0.001), with suggestive enrichment of the TGF-β (FDR = 0.143) and p53 (FDR = 0.229) signaling pathways. On immune deconvolution, POU2F3-high tumours showed a nominal increase in activated dendritic cells, which did not withstand multiple testing correction. POU2F3 protein was detected in 12.4% of tumours and was significantly associated with p53 or RB1 abnormalities (single or double) (P = 0.028).

POU2F3 marks a transcriptionally distinct, early-stage subtype of LUSC with keratinization-related features. Its prognostic relevance appears context-dependent and requires prospective validation in uniformly treated cohorts.