Noncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors.
Noncanonical HPV carcinogenesis drives radiosensitization of head and neck tumors.
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非典型HPV致癌作用驱动头颈部肿瘤的放射增敏。
DOI：
10.1073/pnas.2216532120
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发表时间：
2023-08-08
影响因子：
11.1
通讯作者：
Issaeva, Natalia
中科院分区：
文献类型：
--
作者：
Schrank, Travis P.;Kothari, Aditi;Weir, William H.;Stepp, Wesley H.;Rehmani, Hina;Liu, Xinyi;Wang, Xiaowei;Sewell, Andrew;Li, Xue;Tasoulas, Jason;Kim, Sulgi;Yarbrough, Gray;Xie, Yue;Flamand, Yael;Marur, Shanthi;Hayward, Michele C.;Wu, Di;Burtness, Barbara;Anderson, Karen S.;Baldwin, Albert S.;Yarbrough, Wendell G.;Issaeva, Natalia
人乳头瘤病毒相关性（HPV+）头颈部鳞状细胞癌（HNSCC）是目前最常见的HPV相关性癌症，发病率不断上升。HPV介导的肿瘤发生通常被认为依赖于病毒DNA整合到宿主基因组中、HPV早期基因2（HPV E2）表达的丧失、磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基α（PIK 3CA）的活化和载脂蛋白B mRNA编辑催化多肽（APOBEC）介导的诱变。我们报告了一个HPV+癌亚类的鉴定，其中约45%的HPV+ HNSCC与这些经典特征无关。该亚组中的患者具有稳健改善的临床结果，并且具有此类基因组和转录组特征的细胞模型对辐射的敏感性增加。对HPV+ HNSCC的生物学上不同的肿瘤亚类的识别与对放射治疗的差异反应可能从根本上改变患者的治疗方式。我们分析了来自104个HPV+（人乳头瘤病毒）HNSCC（头颈部鳞状细胞癌）肿瘤的转录数据以及两个公开来源，以确定高度稳健的转录程序（模块），尽管采用了异质性测序和定量方法，但仍可以一致地检测到这些程序。在鉴定的22个模块中，我们发现了一个单一的模块，该模块基于基因表达的双峰模式自然地对HPV+ HNSCC肿瘤进行亚分类，将HPV+ HNSCC生物学的所有非典型特征聚类到一个单一的亚类中，并预测四个独立队列中的患者结局。亚类定义基因集与核因子κ B（NF-κB）靶基因表达密切相关。这种NF-κB模块高表达的肿瘤很少与激活PIK 3CA改变或病毒整合相关，并且还表达更高水平的HPHPV E2，并且具有减少的APOBEC诱变。或者，它们包含NF-κB、TNF受体相关因子3（TRAF 3）和圆柱瘤病（CYLD）以及视网膜母细胞瘤蛋白（RB 1）的关键调节因子的失活改变。在TRAF 3或CYLD实验性耗竭的培养物中的HPV+ HNSCC细胞显示出亚类定义基因的表达增加，以及稳健的放射增敏，从而重现了在患者数据中观察到的肿瘤转录状态和改善的治疗反应。在所有研究的基因组中，甲基化与表达的相关性在定义亚类的NF-κ B相关基因中最强。在NF-κB活性肿瘤中发现肿瘤浸润性CD 4 + T细胞增加和雌激素受体α（ERα）表达增加。基于HPV+ HNSCC相对较高的治愈率，许多机构正在研究降低治疗相关发病率的治疗。基于致癌亚型的肿瘤亚分类可能有助于指导HPV+ HNSCC患者的治疗强度或方式的选择。
Human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is now the most common HPV-associated cancer with increasing incidence. HPV-mediated oncogenesis is generally thought to rely on the integration of the viral DNA into the host genome, loss of HPV early gene 2 (HPV E2) expression, activation of Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), and apolipoprotein B mRNA editing catalytic polypeptide (APOBEC)-mediated mutagenesis. We report the identification of a subclass of HPV+ carcinomas comprising ~45% of HPV+ HNSCC that is not associated with any of these classic features. Patients in this subgroup have robustly improved clinical outcomes, and cell models with genomic and transcriptomic features of this class have increased sensitivity to radiation. The recognition of biologically distinct tumor subclasses of HPV+ HNSCC with differential responses to radiotherapy may fundamentally alter how patients are treated. We analyzed transcriptional data from 104 HPV+ (Human papillomavirus) HNSCC (head and neck squamous cell carcinoma) tumors together with two publicly available sources to identify highly robust transcriptional programs (modules) which could be detected consistently despite heterogeneous sequencing and quantification methodologies. Among 22 modules identified, we found a single module that naturally subclassifies HPV+ HNSCC tumors based on a bimodal pattern of gene expression, clusters all atypical features of HPV+ HNSCC biology into a single subclass, and predicts patient outcome in four independent cohorts. The subclass-defining gene set was strongly correlated with Nuclear factor kappa B (NF-κB) target expression. Tumors with high expression of this NF-κB module were rarely associated with activating PIK3CA alterations or viral integration, and also expressed higher levels of HPHPV E2 and had decreased APOBEC mutagenesis. Alternatively, they harbored inactivating alterations of key regulators of NF-κB, TNF receptor associated factor 3 (TRAF3), and cylindromatosis (CYLD), as well as retinoblastoma protein (RB1). HPV+ HNSCC cells in culture with experimental depletion of TRAF3 or CYLD displayed increased expression of the subclass-defining genes, as well as robust radio-sensitization, thus recapitulating both the tumor transcriptional state and improved treatment response observed in patient data. Across all gene sets investigated, methylation to expression correlations were the strongest for the subclass-defining, NF-κB-related genes. Increased tumor-infiltrating CD4+ T cells and increased Estrogen receptors alpha (ERα) expression were identified in NF-κB active tumors. Based on the relatively high rates of cure in HPV+ HNSCC, deintensification of therapy to reduce treatment-related morbidity is being studied at many institutions. Tumor subclassification based on oncogenic subtypes may help guide the selection of therapeutic intensity or modality for patients with HPV+ HNSCC.
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