Transitional lncRNA Signatures Reveal Distinct Stages of Cancer Progression and Metastasis

Abstract Long non-coding RNAs (lncRNAs) are emerging as key regulators in cancer, influencing gene expression, chromatin remodeling, and signaling. Evidence from The Cancer Genome Atlas (TCGA) and other datasets supports their role in tumor progression. Although the human genome harbors thousands lncRNA genes, only a small subset has been validated in cancer. In this study, we used the LncBook catalog (∼95,000 lncRNAs) to identify ∼12,500 lncRNAs with expression evidence across major TCGA cancer types. These were stratified by clinical annotations, including cancer stage (I–IV) and metastatic state (M0/M1). Using significant differential expression (z-score >|3|) for consecutive transitions, we identified a set of influential transitional lncRNAs (Tr-lncRNAs) that signify cancer transitions. Analyzing seven transitions revealed that over 70% of Tr-lncRNAs were cancer-type specific, while only 2–4% were shared across 17 major cancers. Each cancer type had 30–80 Tr-lncRNAs, with more than half uniquely expressed in one type. Most Tr-lncRNAs were previously uncharacterized. A pan-cancer analysis revealed 14 shared Tr-lncRNAs, including known ones such as XIST and H19. Our findings highlight distinct lncRNA expression patterns during cancer progression and provide new insights into cis-regulatory antisense mechanisms. We discuss the potential of Tr-lncRNAs as diagnostic biomarkers and therapeutic targets in cancer.