文章：

头颈癌的分子结构

The molecular landscape of head and neck cancer

原文发布日期：2018-03-02

DOI: 10.1038/nrc.2018.11

类型: Review Article

开放获取: 否

要点：

1. There are major molecular differences between human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancers, and these underlie the major clinical differences. HPV-positive oropharyngeal cancers are associated with a favourable prognosis.
2. The lack of HPV-positive mucosal precursor changes has hampered investigation of the natural history of HPV-driven oropharyngeal cancers. Current data suggest that the productive infections take place in the oral cavity and transforming infections in a subgroup of epithelial cells mostly found in the tonsils, which are characterized by specific molecular markers.
3. Assessing HPV status in oropharyngeal cancer with the use of immunostaining for the surrogate marker p16^INK4A is appropriate for staging, but additional HPV DNA or RNA testing will be required for treatment de-escalation.
4. Detailed molecular characterization of head and neck cancer revealed that the major cancer genes causing the disease are tumour suppressor genes.
5. Many head and neck cancer genes are involved in cell proliferation and cell cycle control, WNT–β-catenin signalling, cell survival and epigenetic regulation.
6. Head and neck cancer is an unexpectedly heterogeneous disease with at least three genetically defined major subgroups: HPV-positive tumours; HPV-negative tumours with many copy number changes; and copy number alteration-silent, HPV-negative tumours.
7. Besides the classification into three distinct genetic subgroups, both HPV-positive and HPV-negative tumours can be subclassified on the basis of genomic profiling.
8. The many genetic changes in head and neck cancer present an opportunity for immunotherapy with immune checkpoint inhibitors.

要点翻译：

1. 人乳头瘤病毒（HPV）阳性与HPV阴性口咽癌之间存在显著的分子差异，这些差异构成了主要临床表现差异的基础。HPV阳性口咽癌通常预后良好。
2. HPV阳性黏膜前驱病变的缺失阻碍了对HPV驱动型口咽癌自然史的研究。现有数据表明，生产性感染发生在口腔腔隙，而转化性感染则多发生于扁桃体区域的上皮细胞亚群中，这些细胞具有特定的分子标记特征。
3. 通过免疫染色检测替代标志物p16INK4A来评估口咽癌HPV状态适用于分期诊断，但治疗降级策略还需额外进行HPV DNA或RNA检测。
4. 头颈癌的精细分子特征研究显示，导致该疾病的主要癌基因是抑癌基因。
5. 许多头颈癌相关基因参与细胞增殖与细胞周期调控、WNT–β-catenin信号传导、细胞存活及表观遗传调控。
6. 头颈癌是一种异质性极高的疾病，至少存在三个遗传学定义的亚型：HPV阳性肿瘤；伴随大量拷贝数变化的HPV阴性肿瘤；以及拷贝数变异静默型的HPV阴性肿瘤。
7. 除这三种遗传亚型分类外，HPV阳性和HPV阴性肿瘤均可通过基因组谱分析进行进一步亚分类。
8. 头颈癌中存在的多种遗传变异为免疫检查点抑制剂的免疫治疗提供了潜在靶点。

英文摘要：

Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.

摘要翻译： 

头颈部鳞状细胞癌（HNSCC）发生于上呼吸消化道的黏膜内，其异质性出乎意料。经典危险因素为吸烟和酗酒，近年来人乳头瘤病毒（HPV）的作用逐渐显现，尤其在口咽部肿瘤中。HPV相关的口咽癌被视为独立的疾病实体，近期已体现在修订的预后分期系统中，而去强化治疗试验的结果尚待公布。HPV在上呼吸消化道黏膜的致癌机制仍属谜团，但结合最新观察，可提出一种模型。2015年，癌症基因组图谱（TCGA）联盟发布了HNSCC的全面分子目录，未发现可成药的新癌基因高频突变，但证实存在一组预后良好的HPV阴性头颈部肿瘤，其遗传特征独特。基于基因组分析，肿瘤可进一步细分。然而，当前的分子数据浩如烟海，需深入的生物学解读。研究亦明确，HNSCC以高频突变产生新抗原为特征，提示免疫治疗可能有效。2016年，免疫检查点抑制剂的免疫治疗试验首批结果发表，可视为头颈部肿瘤学的范式转变。

原文链接：

The molecular landscape of head and neck cancer