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Updated: Mar 7, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma
Alex Panaccione1, Yi Zhang1, Yanfang Mi1
1Section of Otolaryngology, Department of Surgery, Yale School of Medicine, 789 Howard Avenue, New Haven, CT 06519, USA.
Background:
Mucinous adenocarcinoma of the salivary gland (MAC) is a lethal cancer with unknown molecular etiology and a high propensity to lymph node metastasis. Mostly due to its orphan status, MAC remains one of the least explored cancers that lacks cell lines and mouse models that could help translational and pre-clinical studies. Surgery with or without radiation remains the only treatment modality but poor overall survival (10-year, 44%) underscores the urgent need for mechanism-based therapies.
Methods:
We developed the first patient-derived xenograft (PDX) model for pre-clinical MAC studies and a cell line that produces aggressively growing tumors after subcutaneous injection into nude mice. We performed cytogenetic, exome, and proteomic profiling of MAC to identify driving mutations, therapeutic targets, and pathways involved in aggressive cancers based on TCGA database mining and GEO analysis.
Results:
We identified in MAC KRAS (G13D) and TP53 (R213X) mutations that have been previously reported as drivers in a variety of highly aggressive cancers. Somatic mutations were also found in KDM6A, KMT2D, and other genes frequently mutated in colorectal and other cancers: FAT1, NBEA, RELN, RLP1B, and ZFHX3. Proteomic analysis of MAC implied epigenetic up-regulation of a genetic program involved in proliferation and cancer stem cell maintenance.
Conclusion:
Genomic and proteomic analyses provided the first insight into potential molecular drivers of MAC metastases pointing at common mechanisms of CSC propagation in aggressive cancers. The in vitro/in vivo models that we created should aid in the development and validation of new treatment strategies against MAC.
Insights
Mucinous adenocarcinoma of the salivary gland (MAC) is a lethal cancer. Researchers developed new models and identified KRAS/TP53 mutations, offering insights into aggressive cancer mechanisms and potential therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mucinous adenocarcinoma of the salivary gland (MAC) is a rare and lethal cancer with poor survival rates.
- Its molecular etiology and metastatic potential are poorly understood, hindering therapeutic development.
- The lack of preclinical models limits research into mechanism-based therapies for MAC.
Purpose of the Study:
- To develop the first patient-derived xenograft (PDX) model and cell line for mucinous adenocarcinoma of the salivary gland (MAC).
- To identify driving mutations and therapeutic targets in MAC through comprehensive genomic and proteomic profiling.
- To gain insights into the molecular mechanisms underlying MAC aggressiveness and metastasis.
Main Methods:
- Development of a patient-derived xenograft (PDX) model and a cell line for MAC.
- Cytogenetic, exome, and proteomic profiling of MAC samples.
- Analysis of TCGA and GEO databases to identify common cancer pathways.
Main Results:
- Identification of KRAS (G13D) and TP53 (R213X) mutations, known drivers in aggressive cancers.
- Discovery of somatic mutations in KDM6A, KMT2D, FAT1, NBEA, RELN, RLP1B, and ZFHX3.
- Proteomic analysis indicated epigenetic upregulation of proliferation and cancer stem cell pathways.
Conclusions:
- Genomic and proteomic analyses offer initial insights into MAC metastasis drivers and cancer stem cell propagation.
- The developed in vitro and in vivo models are crucial for validating novel therapeutic strategies against MAC.
