鼻/鼻窦腺癌并不常见，但肠型腺癌（ITAC）很重要。由于这些肿瘤的罕见性，它们的分子特征尚不清楚。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 (HN) 不同解剖位置的 ITAC 的整个转录组和外显子组。本研究使用了 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。对鼻腔位置 ITAC 的分析显示，与其他解剖位置组（有 2909 个亚型特异性差异表达 (DE) 基因）相比，有 410 个亚型特异性差异表达 (DE) 基因和非编码转录本。这些群体共有 872 个基因，其中 17 个高度不同或相反的 DE 基因。全外显子组突变分析显示，MLL3 (KMT2C) 基因是所有研究的腺癌中最常见的功能丧失突变的基因。结果表明，所研究的 HN ITAC 主要是由 MLL3 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，主要通过信号传导、去分化、增殖、迁移、免疫和炎症失调等途径支持致癌性，表明真正的表观遗传事件是这些肠道类型癌症异质多样性的根本原因。本研究的数据构成了了解不同解剖部位正常呼吸道粘膜细胞命运决定和细胞稳态的基础，并显示了不同粘膜成分对 ITAC 病因学/分子病理学的贡献。版权所有 © 2023。由 Elsevier Inc 出版。

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 (HN). Twenty-one HN adenocarcinomas were used in this study, divided into 10 sinonasal adenocarcinomas (SNT) and 11 extrasinonasal (T) HN adenocarcinomas according to anatomic location and histology. Tumor samples along with normal mucosa were microdissected from FFPE samples; 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 to 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) as that with the most frequent loss-of-function mutations in all adenocarcinomas investigated. The results suggest that the HN 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, immune and inflammatory deregulation, indicating a truly epigenetic event as the root cause for the heterogeneous 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.Copyright © 2023. Published by Elsevier Inc.