Abstract：
Adenocarcinomas of the nasal/paranasal sinuses are uncommon, but intestinal-type adenocarcinomas (ITACs) are important. Due to the rarity of these tumors, their molecular profile is not well known. To further investigate the molecular profile and find potential oncogenic drivers, we compared the whole transcriptome and exome of ITACs at different anatomic locations in the head and neck. Twenty-one head and neck adenocarcinomas were used in this study, divided into 10 sinonasal adenocarcinomas (SNT) and 11 extrasinonasal (T) head and neck adenocarcinomas according to anatomic location and histology. Tumor samples along with normal mucosa were microdissected from formalin-fixed, paraffin-embedded samples, and RNA and DNA were subjected to whole-transcriptome and -exome shotgun sequencing. Analysis of ITACs at sinonasal locations showed 410 subtype-specific differentially expressed (DE) genes and noncoding transcripts compared with the group of other anatomic locations, with 2909 subtype-specific DE genes. The groups shared 872 genes, with 17 highly different or opposing DE genes. Whole-exome mutation analysis revealed the gene MLL3 (KMT2C) to be exhibiting the most frequent loss-of-function mutations in all adenocarcinomas investigated. The results suggest that the head and neck ITACs investigated were mainly caused by loss-of-function mutations in MLL3 that disabled chromatin methylation and remodeling of all MLL3-targeted enhancers in the tumors. This changed the activity of multiple genes/gene clusters, supporting oncogenicity mostly via pathways of signaling, dedifferentiation, proliferation, migration, and immune and inflammatory deregulation, indicating a truly epigenetic event as the root cause for the heterogenous diversity of these enteric types of cancer. The data of this study form the basis for understanding cell fate determination and cellular homeostasis in the normal respiratory mucosa at different anatomic sites and show the contribution of different mucosal components to the etiology/molecular pathology of ITAC.
摘要：
鼻/鼻旁窦的腺癌并不常见，但肠型腺癌(ITACs)很重要.由于这些肿瘤的稀有性,他们的分子特征并不为人所知。为了进一步研究分子谱并找到潜在的致癌驱动因素，我们比较了头颈部（HN）不同解剖位置ITAC的整个转录组和外显子组。这项研究使用了21例HN腺癌，根据解剖位置和组织学分为10例鼻窦腺癌（SNT）和11例鼻外（T）HN腺癌。从FFPE样品中显微解剖肿瘤样品和正常粘膜;对RNA和DNA进行全转录组和外显子组鸟枪测序。与其他解剖位置组相比，在鼻窦位置的ITAC分析显示410个亚型特异性差异表达（DE）基因和非编码转录本，具有2909个亚型特异性DE基因。这些群体共有872个基因，有17个高度不同或相反的DE基因。全外显子组突变分析显示基因MLL3（KMT2C）在所有研究的腺癌中具有最常见的功能缺失突变。结果表明，研究的HNITAC主要是由MLL3中的功能丧失突变引起的，该突变使肿瘤中所有MLL3靶向增强子的染色质甲基化和重塑失效。这改变了多个基因/基因簇的活性，主要通过信号通路支持致癌作用，去分化，扩散,迁移,免疫和炎症失调，表明真正的表观遗传事件是这些肠癌类型异质性多样性的根本原因。这项研究的数据为了解不同解剖部位的正常呼吸道粘膜中的细胞命运确定和细胞稳态奠定了基础，并显示了不同粘膜成分对ITAC的病因/分子病理学的贡献。
