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Updated: Jan 13, 2026
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Site-specific prevalence of the NFE2L2 mutation in esophageal squamous cell carcinoma
Akihiko Chida1, Hideyuki Hayashi2,3, Norihito Ishida1
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Background:
Precision medicine for esophageal squamous cell carcinoma (ESCC) has not been implemented owing to a lack of site-specific therapeutic markers and biomarkers. We hypothesized that the genomic background of each subsite of the esophagus might be different, allowing us to develop site-specific treatment strategies (cervical, upper thoracic, middle thoracic and lower thoracic).
Methods:
This was a single-center retrospective cohort study. Patients diagnosed with ESCC who underwent comprehensive genomic profiling (CGP) at Keio University Hospital between April 2017 and March 2024 were recruited. Genomic profiles were analyzed and compared across esophageal subsites.
Results:
Among the 107 patients with ESCC who underwent CGP, 6 were cervical, 16 were upper thoracic, 54 were middle thoracic, and 31 were lower thoracic. The most frequently altered genes were TP53, followed by CDKN2A and NFE2L2. The frequency of NFE2L2 mutations was significantly higher in the middle thoracic region (P = 0.041). The mutation rate increased from Stage I to IV (P = 0.0046). NFE2L2 mutations were rarely observed in early-stage cancers, suggesting that they may subsequently be acquired during growth and metastasis. Furthermore, a significant association was observed between a history of heavy alcohol consumption and NFE2L2 mutations. The overall survival of patients with unresectable or metastatic ESCC harboring NFE2L2 mutations was 12.0 months, compared to 29.7 months in patients without the mutations (HR: 2.37, P = 0.047).
Conclusion:
NFE2L2 mutations were more common in the middle thoracic esophagus, appeared to be associated with tumor progression, and were linked to poor prognosis.
Insights
Genomic analysis of esophageal squamous cell carcinoma (ESCC) reveals NFE2L2 mutations are more frequent in the middle thoracic region and linked to poorer outcomes. This finding may guide site-specific precision medicine strategies for ESCC.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Precision medicine for esophageal squamous cell carcinoma (ESCC) is limited by a lack of site-specific therapeutic markers.
- Genomic differences across esophageal subsites may enable tailored treatment strategies.
Purpose of the Study:
- To investigate the genomic profiles of ESCC across different esophageal subsites.
- To identify potential site-specific biomarkers for ESCC treatment.
Main Methods:
- Retrospective cohort study of 107 ESCC patients undergoing comprehensive genomic profiling (CGP).
- Analysis and comparison of genomic profiles across cervical, upper, middle, and lower thoracic subsites.
- Correlation of genetic alterations with tumor stage, alcohol consumption, and patient survival.
Main Results:
- TP53, CDKN2A, and NFE2L2 were the most frequently altered genes.
- NFE2L2 mutations were significantly more common in the middle thoracic region (P=0.041) and increased with tumor stage (P=0.0046).
- NFE2L2 mutations were associated with heavy alcohol consumption and poorer overall survival in unresectable/metastatic ESCC (12.0 vs. 29.7 months, HR=2.37, P=0.047).
Conclusions:
- NFE2L2 mutations are prevalent in middle thoracic ESCC and associated with tumor progression.
- These mutations correlate with a poorer prognosis in advanced ESCC.
- Findings suggest NFE2L2 as a potential site-specific biomarker for ESCC.
