Comprehensive genomic and transcriptomic analyses reveal prognostic stratification for esophageal squamous cell carcinoma
Recent large-scale multi-omics studies have characterized the heterogeneity of esophageal squamous cell carcinoma (ESCC), but inconsistent clinical management has hindered the identification of prognostic markers and patient stratification. Here, we conducted genomic and transcriptomic profiling of 203 patients from the ECTOP-2002 study with full clinical information. Mutation in the mucin family, as well as APOBEC signature, were associated with poor prognosis. In contrast, activation of the epithelial-keratinization (EpK) pathway was strongly linked to favorable prognosis and lower post-chemotherapy recurrence rates. Independent validation supported S100A8 + S100A9 complex as a key marker of EpK pathway. Furthermore, we established a prognostic stratification system, FU-ESCC subtyping, which defines three subtypes with distinct molecular and clinical features. The EpK-activated subtype retained characteristics of healthy squamous epithelial cells, showed high expression of the S100A8 + S100A9 complex, and was associated with favorable prognosis. The cancer-associated fibroblast (CAF)-enriched subtype showed elevated FAP and Vimentin expression, abundant CAFs, high proliferative activity, and poor prognosis. The immune-desert subtype was characterized by low immune infiltration, suppressed immune signaling, and similarly poor prognosis. Our study provides a valuable resource and insights to better understand ESCC in the era of precision medicine and targeted therapies.
Authors
- Yihua Sun (ORCID: https://orcid.org/0000-0001-8027-2927)
- Tao An (ORCID: https://orcid.org/0000-0003-4341-0029)
- Xiangze Li (ORCID: https://orcid.org/0009-0007-8123-8836)
- Mou Zhang (ORCID: https://orcid.org/0000-0002-6941-7985)
- Midie Xu
- Shiyue Zhang (ORCID: https://orcid.org/0009-0001-5313-9802)
- Yiliang Zhang (ORCID: https://orcid.org/0000-0002-9851-7870)
- Longlong Shao
- Fangqiu Fu (ORCID: https://orcid.org/0000-0001-5791-4741)
- Jian Gao (ORCID: https://orcid.org/0000-0002-0446-7471)
- Yang Zhang (ORCID: https://orcid.org/0000-0002-0098-8974)
- Bin Li (ORCID: https://orcid.org/0009-0008-3791-0936)
- Jun Wang (ORCID: https://orcid.org/0000-0001-5322-5244)
- Hang Li (ORCID: https://orcid.org/0000-0003-4905-2242)
- Yue Zhao (ORCID: https://orcid.org/0000-0003-3645-2634)
- Ting Ye (ORCID: https://orcid.org/0000-0002-5704-400X)
- Haiquan Chen (ORCID: https://orcid.org/0000-0001-7846-257X)
- Hong Hu (ORCID: https://orcid.org/0000-0003-3497-0454)
- Kuaile Zhao (ORCID: https://orcid.org/0000-0003-1271-2278)
- Zhiwei Cao (ORCID: https://orcid.org/0000-0003-1165-1928)
- Ziling Huang (ORCID: https://orcid.org/0000-0003-3241-7911)
- Longfei Ma (ORCID: https://orcid.org/0000-0003-3419-6403)
- Chong Dai (ORCID: https://orcid.org/0000-0003-3423-8351)
- Longsheng Miao
- Teng Yang
- Xiaoyang Luo
- Jia-Qing Xiang
- Yawei Zhang (ORCID: https://orcid.org/0009-0000-1674-7107)
- Xiaoxiao Shang
- Qiming Wang (ORCID: https://orcid.org/0009-0002-3863-0262)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Fudan University Shanghai Cancer Center (CN)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41392-025-02306-8
- Citations
- 5
- Primary Topic
- Esophageal Cancer Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 10.03
Funders
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China
- Fudan University