Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer

Gu, W.; Bhangale, A. D.; Du, X.; Deng, X.; Gensterblum-Miller, E. U.; Currie, J.; Brummel, C. V.; Nyabashi, V.; Buchakjian, M.; Casper, K. A.; Chinn, S. E.; Forner, D.; Malloy, K. M.; Mierzwa, M. L.; Prince, M. E.; Shah, J. L.; Shuman, A. G.; Stucken, C. L.; Swiecicki, P. L.; Worden, F. P.; Yalamanchi, P.; McHugh, J. B.; Kuhs, K. A.; Boyle, A. P.; Jiang, H.; Neal, M. E.; Spector, M. E.; Mills, R. E.; Brenner, C. J.

doi:10.64898/2026.10.03.756294

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bioRxiv · 10.64898/2026.10.03.756294

Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer

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Abstract

Viral integration is common in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC), but its structural and clinical significance remains unclear. We integrated targeted capture sequencing of 197 HPV+ OPSCCs with long-read nanopore sequencing of 17 tumors and models to characterize HPV-host rearrangements. We developed a novel quantitative informatics framework that classifies integration structures as Type1 (simple, single/low-copy) or Type2 (clustered, high-copy, rearranged). HPV integration occurred in 83% of tumors, with recurrent hotspots including TP63, MYC, CD274, TRAF2, and KMT2C. Type2 events were enriched for HPV E2 disruption, focal human amplifications, preferential transcription, and noncanonical HPV-host RNA fusion isoforms. Type2 tumors showed increased HPV oncogene expression and activation of MYC, NF-{kappa}B/TNF, PI3K-AKT-mTOR, Hippo/YAP-TAZ, and epithelial stemness programs. Multi-region and longitudinal analyses revealed intratumoral heterogeneity and clonal selection of Type2 architectures during progression, supporting integration structure as a potential marker of aggressive behavior and risk stratification.

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Gu, W., Bhangale, A. D., Du, X., Deng, X., Gensterblum-Miller, E. U., Currie, J., Brummel, C. V., Nyabashi, V., Buchakjian, M., Casper, K. A., Chinn, S. E., Forner, D., Malloy, K. M., Mierzwa, M. L., Prince, M. E., Shah, J. L., Shuman, A. G., Stucken, C. L., Swiecicki, P. L., Worden, F. P., Yalamanchi, P., McHugh, J. B., Kuhs, K. A., Boyle, A. P., Jiang, H., Neal, M. E., Spector, M. E., Mills, R. E., Brenner, C. J.. 2026-10-10. Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer. https://doi.org/10.64898/2026.10.03.756294

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