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Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer

Author

Listed:
  • Noah Sasa

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    the University of Tokyo
    RIKEN Center for Integrative Medical Sciences)

  • Toshihiro Kishikawa

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine
    Aichi Cancer Center Hospital)

  • Masashi Mori

    (Osaka University Graduate School of Medicine)

  • Rie Ito

    (Osaka University Graduate School of Medicine
    Osaka Rosai Hospital)

  • Yumie Mizoro

    (the University of Tokyo)

  • Masami Suzuki

    (Osaka University Graduate School of Medicine)

  • Hirotaka Eguchi

    (Osaka University Graduate School of Medicine)

  • Hidenori Tanaka

    (Osaka University Graduate School of Medicine)

  • Takahito Fukusumi

    (Osaka University Graduate School of Medicine)

  • Motoyuki Suzuki

    (Osaka University Graduate School of Medicine)

  • Yukinori Takenaka

    (Osaka University Graduate School of Medicine)

  • Keisuke Nimura

    (Osaka University Graduate School of Medicine
    Gunma University)

  • Yukinori Okada

    (Osaka University Graduate School of Medicine
    the University of Tokyo
    RIKEN Center for Integrative Medical Sciences
    Osaka University)

  • Hidenori Inohara

    (Osaka University Graduate School of Medicine)

Abstract

Integration of human papillomavirus (HPV) into the host genome drives HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC). Whole-genome sequencing of 51 tumors revealed intratumor heterogeneity of HPV integration, with 44% of breakpoints subclonal, and a biased distribution of integration breakpoints across the HPV genome. Four HPV physical states were identified, with at least 49% of tumors progressing without integration. HPV integration was associated with APOBEC-induced broad genomic instability and focal genomic instability, including structural variants at integration sites. HPV+ HNSCCs exhibited almost no smoking-induced mutational signatures. Heterozygous loss of ataxia-telangiectasia mutated (ATM) was observed in 67% of tumors, with its downregulation confirmed by single-cell RNA sequencing and immunohistochemistry, suggesting ATM haploinsufficiency contributes to carcinogenesis. PI3K activation was the major oncogenic mutation, with JAK-STAT activation in tumors with clonal integration and NF-kappa B activation in those without. These findings provide valuable insights into HPV integration in HPV+ HNSCC.

Suggested Citation

  • Noah Sasa & Toshihiro Kishikawa & Masashi Mori & Rie Ito & Yumie Mizoro & Masami Suzuki & Hirotaka Eguchi & Hidenori Tanaka & Takahito Fukusumi & Motoyuki Suzuki & Yukinori Takenaka & Keisuke Nimura &, 2025. "Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56150-z
    DOI: 10.1038/s41467-025-56150-z
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