Transcriptomic clustering identifies shared molecular programs across Human Papillomavirus-driven oropharyngeal and cervical carcinomas

Human Papillomavirus (HPV) drives carcinogenesis in distinct anatomical sites, including the oropharynx and cervix, yet the molecular convergence between these tumors remains poorly defined. We integrated transcriptomic data from 553 HPV-positive oropharyngeal carcinomas (OPC) and 488 HPV-positive cervical carcinomas (CC), including a newly profiled institutional cohort, to identify shared molecular programssubtypes with clinical and biological significance. Unsupervised consensus clustering revealed three gene-expression clusters in each tumor type. Subclass mapping demonstrated strong cross-cancer correspondence between OPC2–CC1 (p=0.001) and OPC3–CC2 (p=0.008), supporting the presence of shared conserved transcriptional programs across tumor sites. Immune and functional profiling revealed immune-cold, radioresistant clusters enriched for TNFα–NFκB, epithelial–mesenchymal transition, and hypoxia signaling, and immune-active, radiosensitive clusters characterized by interferon and IL6–JAK–STAT3 pathways. Distinct radiosensitivity and immunogenicity patterns were validated using Radiosensitivity Index and Immunophenoscore metrics. These results define a significant concordance overlap of transcriptomic features for HPV-driven OPC and CC, highlighting two cross-cancer cluster correspondences paired molecular subtypes that are independent of tissue origin and reflect associated with common immune and therapeutic vulnerabilities. This integrative analysis supports the use of cross-cancer transcriptomic clustering to refine prognostic and therapeutic strategies for HPV-associated carcinomas.