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Molecular Diagnostics

Oncogenic NFE2L2 mutations in plasma ctDNA and tumors are predictors and prognosticators of chemoradiation therapy in resectable esophageal squamous cell carcinoma

British Journal of Cancer volume 133, pages 1046–1055 (2025)Cite this article

Subjects

Abstract

Background

The poor prognosis of resectable esophageal squamous cell carcinoma (ESCC) poses an unmet need to identify early predictive and prognostic genomic biomarkers to improve treatment outcome and risk stratification.

Methods

Mutational profiling was performed for 171 ESCC patients receiving curative neoadjuvant chemoradiation treatment (nCRT). The discovery cohort included 100 ESCC formalin-fixed paraffin-embedded (FFPE) tumor specimens; the validation FFPE cohort consisted of serial ctDNA samples from 71 patients.

Results

The discovery cohort identified hot-spot oncogenic NFE2L2 mutations exclusively localized at DLG and ETGE KEAP1-binding motifs in poor responders associated with incomplete pathological response (P = 0.004). Patients with NFE2L2 mutations in two independent FFPE cohorts had about 2-fold higher risk of death and recurrence. Serial ctDNA analysis further demonstrated oncogenic NFE2L2 mutations detected at post-nCRT were independent prognosticators for recurrence (HR = 5.90; P = 0.005) and survival (HR = 4.75; P = 0.013). Risk stratification based on pathological T and N stages, positive FFPE (HR = 4.50) and ctDNA NFE2L2 mutations (HR = 8.50) identified high-risk groups for recurrence (P = 0.001). Combined FFPE and ctDNA NFE2L2 mutation status predicted nCRT responses (P = 0.05) by ROC analysis.

Conclusions

Tracking oncogenic NFE2L2 mutations at pre-treatment and post-surgery or serial ctDNA monitoring during treatment are useful nCRT predictors and independent prognosticators of survival for locally advanced ESCC.

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Fig. 1
Fig. 2: Kaplan-Meier survival analysis of NFE2L2 mutations in the DLG/ETGE motifs across different patient cohorts.
Fig. 3
Fig. 4: Multi-panel analysis of NFE2L2 mutation data and patient outcomes.

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Data availability

All data supporting the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The study is funded by Hong Kong Research Grants Council Theme-Based Research Scheme grant number T12-701/17-R to MLL.

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Author notes

  1. These authors contributed equally: Josephine Mun-Yee Ko, Chen Guo.

Authors and Affiliations

  1. Department of Clinical Oncology, Centre of Cancer Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), Hong Kong, People’s Republic of China

    Josephine Mun-Yee Ko, Chen Guo, Alvin Ka-Kiu Leung, Steve Chun-Yin Chan, Lihua Tao, Hoi-Yan Ng, Carissa Wing-Yan Wong, Ka-On Lam, Dora Lai-Wan Kwong, Wei Dai & Maria Li Lung

  2. Division of Anatomical Pathology, Queen Mary Hospital, Hong Kong (Special Administrative Region), Hong Kong, People’s Republic of China

    Anthony Wing-Ip Lo

  3. Department of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong (Special Administrative Region), Hong Kong, People’s Republic of China

    Simon Law, Ian Yu-Hong Wong, Claudia Lai-Yin Wong, Fion Siu-Yin Chan, Kwan Kit Chan & Tsz Ting Law

  4. Department of Cancer Molecular Pathology, School of Medicine and Dentistry and Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia

    Alfred King-Yin Lam

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Contributions

Conceptualization: MLL, JMYK, KOL Methodology: JMYK, CG, HYN, WD Formal analysis: CG, AKKL, LT, AKYL Investigation: CG, AKKL, SCYL, LT, CWYW, AKYL Resources: AWIL, SL, IYHW, CLYW, FSYC, KKC, TTL, KOL, DLWK Data curation: AWIL, SL, IYHW, CLYW, FSYC, KKC, TTL, KOL, DLWK Writing – original draft: JMYK, CG Writing – review & editing: JMYK, MLL Visualization: JMYK, CG Supervision: MLL, JMYK Project administration: MLL, JMYK Funding acquisition: MLL, SL.

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Correspondence to Josephine Mun-Yee Ko.

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Ko, J.MY., Guo, C., Leung, A.KK. et al. Oncogenic NFE2L2 mutations in plasma ctDNA and tumors are predictors and prognosticators of chemoradiation therapy in resectable esophageal squamous cell carcinoma. Br J Cancer 133, 1046–1055 (2025). https://doi.org/10.1038/s41416-025-03113-2

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