Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer
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 i...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56150-z |
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| author | 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 Hidenori Inohara |
| author_facet | 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 Hidenori Inohara |
| author_sort | Noah Sasa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dd458577050d4cfebb1d22d0ef5fcea8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dd458577050d4cfebb1d22d0ef5fcea82025-01-26T12:41:41ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-025-56150-zIntratumor heterogeneity of HPV integration in HPV-associated head and neck cancerNoah Sasa0Toshihiro Kishikawa1Masashi Mori2Rie Ito3Yumie Mizoro4Masami Suzuki5Hirotaka Eguchi6Hidenori Tanaka7Takahito Fukusumi8Motoyuki Suzuki9Yukinori Takenaka10Keisuke Nimura11Yukinori Okada12Hidenori Inohara13Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Genome Informatics, Graduate School of Medicine, the University of TokyoDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineDepartment of Genome Biology, Osaka University Graduate School of MedicineDepartment of Statistical Genetics, Osaka University Graduate School of MedicineDepartment of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-56150-z |
| spellingShingle | 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 Hidenori Inohara Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer Nature Communications |
| title | Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer |
| title_full | Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer |
| title_fullStr | Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer |
| title_full_unstemmed | Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer |
| title_short | Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer |
| title_sort | intratumor heterogeneity of hpv integration in hpv associated head and neck cancer |
| url | https://doi.org/10.1038/s41467-025-56150-z |
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