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PreprintCC BY-NCbioRxiv

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

  • W. Gu
  • A. D. Bhangale
  • X. Du
  • X. Deng
  • E. U. Gensterblum-Miller
  • J. Currie
  • C. V. Brummel
  • V. Nyabashi
  • M. Buchakjian
  • K. A. Casper
  • S. E. Chinn
  • D. Forner
17 more authors
  • K. M. Malloy
  • M. L. Mierzwa
  • M. E. Prince
  • J. L. Shah
  • A. G. Shuman
  • C. L. Stucken
  • P. L. Swiecicki
  • F. P. Worden
  • P. Yalamanchi
  • J. B. McHugh
  • K. A. Kuhs
  • A. P. Boyle
  • H. Jiang
  • M. E. Neal
  • M. E. Spector
  • R. E. Mills
  • C. J. Brenner1
  1. 1University of Michigan
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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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Cite

BibTeXRIS
BibTeX
@misc{gu2026spatiotemporal,
  title = {{Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer}},
  author = {W. Gu and A. D. Bhangale and X. Du and X. Deng and E. U. Gensterblum-Miller and J. Currie and C. V. Brummel and V. Nyabashi and M. Buchakjian and K. A. Casper and S. E. Chinn and D. Forner and K. M. Malloy and M. L. Mierzwa and M. E. Prince and J. L. Shah and A. G. Shuman and C. L. Stucken and P. L. Swiecicki and F. P. Worden and P. Yalamanchi and J. B. McHugh and K. A. Kuhs and A. P. Boyle and H. Jiang and M. E. Neal and M. E. Spector and R. E. Mills and C. J. Brenner},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.03.756294},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.03.756294v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Spatiotemporal Heterogeneity of HPV Integration Architectures Drive Oncogenic Features of Oropharyngeal Cancer
AU  - W. Gu
AU  - A. D. Bhangale
AU  - X. Du
AU  - X. Deng
AU  - E. U. Gensterblum-Miller
AU  - J. Currie
AU  - C. V. Brummel
AU  - V. Nyabashi
AU  - M. Buchakjian
AU  - K. A. Casper
AU  - S. E. Chinn
AU  - D. Forner
AU  - K. M. Malloy
AU  - M. L. Mierzwa
AU  - M. E. Prince
AU  - J. L. Shah
AU  - A. G. Shuman
AU  - C. L. Stucken
AU  - P. L. Swiecicki
AU  - F. P. Worden
AU  - P. Yalamanchi
AU  - J. B. McHugh
AU  - K. A. Kuhs
AU  - A. P. Boyle
AU  - H. Jiang
AU  - M. E. Neal
AU  - M. E. Spector
AU  - R. E. Mills
AU  - C. J. Brenner
PY  - 2026
DA  - 2026/10/03
PB  - bioRxiv
DO  - 10.64898/2026.10.03.756294
UR  - https://www.biorxiv.org/content/10.64898/2026.10.03.756294v1
AB  - 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.
ER  -