A systems biology approach to uncover CNV-driven lncRNA regulatory networks in HPV-associated head and neck squamous cell carcinoma

Copy number variations (CNVs) have been identified as critical contributors to head and neck squamous cell carcinoma (HNSCC) pathogenesis. Multi-omics analyses offer a comprehensive understanding of its underlying genetic complexities. Therefore, this study aims to examine the CNV-driven long non-coding RNAs (lncRNAs) influencing global regulatory triplet networks (lncRNA–miRNA–mRNA) in HPV-positive and HPV-negative HNSCC subtypes. Differential expression of miRNAs, mRNAs, and CNV-associated lncRNAs were identified using TCGA-HNSCC data. Subsequently, target prediction analyses enabled the construction of CNV-driven global triplet networks specific to HPV status. Gene Ontology (GO) analysis revealed that mRNAs in HPV-positive HNSCC were enriched in cancer-associated processes such as cell proliferation and extracellular matrix (ECM) organization. In contrast, those in HPV-negative HNSCC were primarily enriched in tissue remodeling, development, and cancer progression. KEGG pathway enrichment further supported these findings. The relationship between the CNV of lncRNA MCCC1-AS1 and its expression has revealed that there was no correlation between them in the HPV-positive HNSCC, while in the HPV-negative HNSCC, the gene expression of lncRNA MCCC1-AS1 was correlated with the CNV status. Survival analysis disclosed that the patient with a copy number gain of MCCC1-AS1 was associated with a shorter survival time, suggesting its potential as a prognostic biomarker. These findings highlight the significance of CNV-driven lncRNAs in the molecular landscape of HNSCC and suggest that MCCC1-AS1 may serve as a promising target for further investigation in diagnostic and therapeutic strategies.