Related Experiment Video
Updated: Jul 12, 2025
Therapy Testing in a Spheroid-based 3D Cell Culture Model for Head and Neck Squamous Cell Carcinoma
Published on: April 20, 2018
Intestinal-Type Adenocarcinoma in Head and Neck: Dissecting Oncogenic Gene Alterations Through Whole Transcriptome
Diana Bell1, Achim H Bell2, Randal S Weber3
1Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California.
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.
Insights
Intestinal-type adenocarcinomas (ITACs) in the head and neck are often driven by MLL3 gene mutations. These mutations disrupt epigenetic regulation, impacting cell signaling and proliferation in these rare cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Intestinal-type adenocarcinomas (ITACs) of the nasal/paranasal sinuses are rare but significant head and neck tumors.
- The molecular underpinnings of these ITACs remain largely unknown due to their rarity.
Purpose of the Study:
- To investigate the molecular profile of head and neck ITACs.
- To identify potential oncogenic drivers and understand the epigenetic basis of ITAC heterogeneity.
Main Methods:
- Whole transcriptome and whole exome shotgun sequencing were performed on 21 head and neck adenocarcinomas (10 sinonasal, 11 extrasinonasal).
- Tumor and normal mucosa samples were microdissected from formalin-fixed, paraffin-embedded tissues.
- Differential gene expression analysis and mutation analysis were conducted.
Main Results:
- Analysis revealed distinct gene expression profiles between sinonasal ITACs and extrasinonasal ITACs.
- Loss-of-function mutations in the MLL3 (KMT2C) gene were the most frequent finding across all investigated adenocarcinomas.
- MLL3 mutations were associated with impaired chromatin methylation and remodeling, affecting multiple oncogenic pathways.
Conclusions:
- Head and neck ITACs are frequently driven by MLL3 loss-of-function mutations, leading to epigenetic dysregulation.
- These epigenetic alterations impact key cellular processes including signaling, proliferation, and immune response, contributing to tumor heterogeneity.
- The findings provide insights into the molecular etiology of ITACs and cellular homeostasis in respiratory mucosa.
More Related Videos
Related Concept Videos
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...