TUSC7 expression and mutational profile define its potential as a diagnostic and therapeutic biomarker in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases and remains the leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, early diagnosis and prediction of treatment response remain major challenges. Long non-coding RNAs (lncRNAs) are increasingly recognized as tissue-specific regulators of gene expression with growing relevance in cancer biology, making them attractive candidates for biomarker discovery. To identify functionally relevant lncRNA variants in NSCLC, we analyzed targeted DNA sequencing data from 39 NSCLC-derived cell lines and 70 primary tumors, including matched adjacent non-tumoral tissues to enable somatic variant identification. A somatic variant in the lncRNA TUSC7 was ranked among the top candidates, supported by high functional impact scores. Located in exon 4, a region previously reported as functionally relevant, the mutation was predicted to alter RNA secondary structure and was experimentally associated with enhanced cell fitness under genotoxic stress. TUSC7 variant altered lncRNA stability under genotoxic stress, supporting a possible TUSC7 DNA damage-related role. In addition, in our independent cohort, TUSC7 expression was significantly downregulated in tumor samples compared with matched adjacent non-tumoral tissue, a pattern that was independently validated using transcriptomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Receiver operating characteristic (ROC) analysis yielded AUC values above 0.96 in both datasets, underscoring the strong diagnostic potential of TUSC7 expression in NSCLC. Together, these findings position TUSC7 as a promising biomarker for tumor detection and a potential candidate for therapeutic stratification.