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

Noah Sasa, Toshihiro Kishikawa, Masashi Mori, Rie Ito, Yumie Mizoro, Masami Suzuki, Hirotaka Eguchi, Hidenori Tanaka, Takahito Fukusumi, Motoyuki Suzuki, Yukinori Takenaka, Keisuke Nimura, Yukinori Okada () and Hidenori Inohara ()
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Noah Sasa: Osaka University Graduate School of Medicine
Toshihiro Kishikawa: Osaka University Graduate School of Medicine
Masashi Mori: Osaka University Graduate School of Medicine
Rie Ito: Osaka University Graduate School of Medicine
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
Yukinori Okada: Osaka University Graduate School of Medicine
Hidenori Inohara: Osaka University Graduate School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56150-z

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