PO.MCB08.02 · 分子与细胞生物学
人类与病毒全基因组测序确定HPV和APOBEC为鼻窦鳞状细胞癌的致癌驱动因素
Human and viral whole genome sequencing identify HPV and APOBEC as oncogenic drivers in sinonasal squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
鼻窦鳞状细胞癌（SNSCC）是一种罕见的侵袭性恶性肿瘤，其分子特征描述有限。新出现的证据提示人乳头瘤病毒（HPV）参与其中一部分病例，但病毒与宿主因素之间的基因组相互作用仍未得到充分阐明。
方法：
我们对21例SNSCC肿瘤及其匹配的正常样本进行了宿主与病毒配对全基因组测序（WGS），包括超深度病毒WGS（10,000×）和全面的HPV PCR基因分型。使用成熟的计算流程分析了体细胞突变、病毒整合、结构变异和突变特征。
结果：
21例肿瘤中有18例（86%）经WGS或PCR检测为HPV阳性，各检测方法间一致性达94%。与HPV16占主导地位的口咽鳞状细胞癌（OPSCC）不同，SNSCC表现出九种HPV基因型，包括HPV11、18、35、39、45、51、56和59。大多数HPV阳性肿瘤中检测到病毒整合事件，包括一个以染色体外DNA（ecDNA）形式扩增的HPV45-TP63融合，据我们所知，这是SNSCC中首个HPV相关的ecDNA样扩增子。多基因型感染表现为单一优势整合型，表明通常由一个“驱动”基因型启动肿瘤发生。宿主突变分析揭示了PIK3CA、CHEK2和KDM6A的复发性克隆突变，且在高风险HPV+病例中TP53和CDKN2A改变减少。突变特征分析确定了以APOBEC3活性为主的特征，独立于吸烟，且该活性延伸至病毒基因组，为宿主-病毒并发的APOBEC突变提供了直接证据。结构变异常见，包括局灶性PTEN缺失以及染色体碎裂（chromothripsis）和染色体丛集（chromoplexy）等复杂重排，凸显了普遍存在的基因组不稳定性。
结论：
人类与病毒配对WGS揭示，HPV通过多样的基因型、APOBEC介导的突变以及整合相关的ecDNA形成来驱动SNSCC的肿瘤发生。这些机制将已知的病毒致癌谱扩展至口咽以外，突出了基因组不稳定性的新途径，并支持将广泛的HPV基因分型和病毒基因组检测纳入SNSCC的诊断和转化框架。
查看英文原文 English abstract
Background:
Sinonasal squamous cell carcinoma (SNSCC) is a rare, aggressive malignancy with limited molecular characterization. Emerging evidence implicates human papillomavirus (HPV) in a subset of cases, but the genomic interplay between viral and host factors remains poorly defined.
Methods:
We performed paired host and viral whole-genome sequencing (WGS) on 21 SNSCC tumors with matched normal samples, including ultra-deep viral WGS (10,000×) and comprehensive HPV PCR genotyping. Somatic mutations, viral integration, structural variants, and mutational signatures were analyzed using established computational pipelines.
Results:
Eighteen of 21 (86%) tumors were HPV-positive by WGS or PCR, with 94% concordance across assays. Unlike oropharyngeal squamous cell carcinoma (OPSCC), where HPV16 predominates, SNSCC exhibited nine HPV genotypes, including HPV11, 18, 35, 39, 45, 51, 56, and 59. Viral integration events were detected in most HPV-positive tumors, including an HPV45-TP63 fusion amplified as extrachromosomal DNA (ecDNA), representing, to our knowledge, the first HPV-associated ecDNA-like amplicon in SNSCC. Multi-genotype infections showed a single dominant integrating type, indicating that one “driver” genotype typically initiates tumorigenesis. Host mutational analysis revealed recurrent clonal mutations in PIK3CA, CHEK2, and KDM6A, with depletion of TP53 and CDKN2A alterations in high-risk HPV+ cases. Mutational signature analysis identified predominant APOBEC3 activity, independent of smoking, which extended to viral genomes, providing direct evidence of concurrent host-virus APOBEC mutagenesis. Structural variants were common, including focal PTEN loss and complex rearrangements such as chromothripsis and chromoplexy, underscoring pervasive genomic instability.
Conclusions:
Paired human and viral WGS reveals that HPV drives tumorigenesis in SNSCC through diverse genotypes, APOBEC-mediated mutagenesis, and integration-linked ecDNA formation. These mechanisms expand the known spectrum of viral oncogenesis beyond the oropharynx, highlighting novel routes of genomic instability and supporting the inclusion of broad HPV genotyping and viral-genomic assays in diagnostic and translational frameworks for SNSCC.
利益披露 Disclosure
H. B. Chong, None..
M. E. Bryan, None..
M. Lin, None..
M. Gohar, None..
W. C. Faquin, None..
J. S. Lewis, None..
D. Faden, None.