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, Hidenori Inohara
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. The integration of human papillomavirus (HPV) drives HPV-positive head and neck squamous cell carcinoma (HPV+ HNSCC). Here, the authors perform genomic analysis to investigate HPV integration in patients with HPV+ HNSCC, identifying intratumor heterogeneity and biased distribution of HPV integration.