SMAD4 mRNA expression as a diagnostic biomarker in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide, largely due to late-stage diagnosis. Although histopathology is the gold standard, there is a need for reliable molecular biomarkers to improve early detection and support less invasive diagnostic strategies. SMAD4, a known tumor suppressor, has been implicated in cancer progression, but its diagnostic relevance in NSCLC requires further investigation. This study aimed to evaluate SMAD4 mRNA expression in NSCLC and assess its association with clinicopathological features and its potential as a tissue-based diagnostic biomarker. METHODS AND RESULTS: SMAD4 mRNA expression was quantified using qPCR in human lung cell lines and tissue samples from 49 NSCLC patients. Findings were validated using transcriptomic datasets from TCGA and GTEx. Associations with clinicopathological parameters were analyzed, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Proteomic validation was performed using CPTAC data. SMAD4 mRNA expression was significantly downregulated in NSCLC tissues compared to adjacent non-tumor tissues, consistent across clinical samples, cell lines, and public datasets. Expression levels varied significantly across histological subtypes and tumor grades. ROC analysis demonstrated good discriminatory ability in the patient cohort (AUC = 0.7995; 95% CI: 0.7056-0.8933), which was confirmed in the GSE32863 validation cohort (AUC = 0.8047; 95% CI: 0.7236-0.8858). Analysis of publicly available CPTAC proteomic data confirmed reduced SMAD4 protein levels, supporting concordant transcriptomic and proteomic downregulation. CONCLUSIONS: SMAD4 mRNA shows promise as a diagnostic biomarker for NSCLC. Further validation in larger cohorts and exploration of its application in minimally invasive diagnostics, such as liquid biopsy, are warranted.