LncRNA CDKN2B-AS1 C-Allele: A High-Risk Genetic Determinant in Cancer Susceptibility and Progression Impacting Immune Cell Modulation Dynamics with Therapeutic Implications

Abstract Examining LncRNA-driven cancer biology, our study represents the first comprehensive investigation of the LncRNA CDKN2B-AS1 across multiple cancer types, revealing its genetic basis for cancer susceptibility, and associations with thromboembolic risks and immunological dynamics. Stratification across hematological and non-hematological cancers revealed predominant prevalence rates of the CDKN2B-AS1 C-allele, notably higher in solid tumor malignancies, peaking at 86.8% in colorectal carcinoma (CRC). CRC-C-carriers exhibited worse outcomes, marked by reduced overall survival, increased venous-thromboembolism, elevated frequencies of thromboembolic-associated gene polymorphisms and BRAF mutations, and decreased MSI-H. Key tumor progression aspects in CRC-C-carriers included an inflammatory profile (reduced Th2 and increased Th1/Th17 cells), angiogenesis and endothelial activity (elevated CD14+, CD31+, CD144+, and VEGFR2+ cells), decreases in tumor suppressor-CD146 + cells (elevated tissue-adherent TA-EPCs lacking CD146), and marked elevation in tumor activity markers (Ki-67, CEA, CA 19-9, EGFR, VEGF-A, PD-1, and CTLA-4). Palbociclib significantly improved progression-free survival relative to baseline, primarily through suppression of tumor cell proliferation, with a more pronounced clinical and biomarker response observed in CDKN2B-AS1 non-C-allele carriers, whereas C-allele carriers exhibited an attenuated response consistent with relative treatment resistance. This underscores the multifaceted role of LncRNA CDKN2B-AS1, presenting it not just as a genetic determinant but also as a potential prognostic biomarker in cancer dynamics, paving the way for targeted personalized interventions, representing promising advancements in cancer therapeutics.