Abstract Colorectal cancer (CRC) exhibits significant inter-patient heterogeneity, limiting the efficacy of modern targeted and immunotherapies. Advances in genomics continue to improve our understanding of CRC. Long non-coding RNAs (lncRNAs) are emerging as key regulators of cancer metabolism and immunity. We evaluated the systems-level role and translational potential of a LINC00092-centered multiomics signature as a clinically tractable biomarker. Under an IRB approved protocol at Augusta University, we profiled 50 paired FFPE CRC tumor and normal-adjacent tissues using a NanoString assay and 8-plex multiplex immunofluorescence spatial imaging. For orthogonal validation, we analyzed 304 TCGA-COAD tumors to identify a LINC00092-centered gene signature, infer pathway flux via PROGENy, characterize metabolic enrichment, and score MHC-I/II, antigen-processing, checkpoint, and immunoproteasome programs. In our paired cohort and TCGA, LINC00092 expression was significantly higher in NAT (normal-adjacent tissue) than in matched tumors, consistent with a NAT-enriched state. LINC00092-high tumors retained elements of this state, whereas LINC00092-low tumors showed a distinct, alternate state. Immune cell profiling and deconvolution revealed distinct immune composition with altered inflammatory signatures in LINC00092-low tumors. LINC00092-high tumors displayed suppression of EGFR/PI3K/MAPK and hypoxia/JAK-STAT signaling with preserved pro-apoptotic (e.g., TRAIL/p53) activity. Concurrently, they exhibited higher MHC-II and checkpoint scores but reduced immunoproteasome activity, defining an antigen-presenting, T cell-modulated, checkpoint-rich state. In contrast, LINC00092-low tumors clustered into a hyperproliferative, hypoxia-adapted, immune-cold/immunoproteasome-high phenotype. Metabolic enrichment supported a lipid- and nucleotide-centric reprogramming in LINC00092-high tumors, with increased fatty acid oxidation, sphingolipid and eicosanoid pathways, and pyrimidine synthesis, indicating a distinct immunometabolic mode rather than purely hyperproliferative growth. In summary, a LINC00092-based multiomics signature, measurable in routine FFPE tissue, separates CRC tumors into groups with distinct signaling, metabolic, and immune profiles. This signature can help stratify patients for pro-apoptotic therapies, immunotherapy, and rational drug combinations. Citation Format: Pankaj Kumar Ahluwalia, Alicia Walker, Sade Logan, Denton Lord, Shamia Jordan, Kimya Jones, Ashis Mondal, Ravindra Kolhe. Exploring a LINC00092-associated multiomics signature as a clinically tractable biomarker in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7909.
Ahluwalia et al. (Fri,) studied this question.