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Molecular Diagnostics

Clinical assessment of the miR-34, miR-200, ZEB1 and SNAIL EMT regulation hub underlines the differential prognostic value of EMT miRs to drive mesenchymal transition and prognosis in resected NSCLC

Abstract

Background

Patients with non-small cell lung cancer (NSCLC) receiving curative surgery have a risk of relapse, and adjuvant treatments only translate into a 5% increase in 5-year survival. We assessed the clinical significance of epithelial–mesenchymal transition (EMT) and explored its association with the [SNAIL/miR-34]:[ZEB/miR-200] regulation hub to refine prognostic information.

Methods

We validated a 7-gene EMT score using a consecutive series of 176 resected NSCLC. We quantified EMT transcription factors, microRNAs (miRs) of the miR-200, miR-34 families and miR-200 promoter hypermethylation to identify outcome predictors.

Results

Most tumours presented with an EMT-hybrid state and the EMT score was not predictive of outcome. Individually, all miR-200 were inversely associated with the EMT score, but only chromosome-1 miRs, miR-200a, b, 429, were associated with disease-free survival (p = 0.08, 0.05 and 0.025) and overall survival (p = 0.013, 0.003 and 0.006). We validated these associations on The Cancer Genome Atlas data. Tumour unsupervised clustering based on miR expression identified two good prognostic groups, unrelated to the EMT score, suggesting that miR profiling may have an important clinical value.

Conclusion

miR-200 family members do not have similar predictive value. Core EMT-miR, regulators and not EMT itself, identify NSCLC patients with a low risk of relapse after surgery.

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Fig. 1: Correlation matrix of miR-34, miR-200, promoter methylation, epithelial and mesenchymal marker expression.
Fig. 2: Unsupervised hierarchical clustering based on miR-34, miR-200 expression and promoter methylation status.
Fig. 3: Kaplan–Meier OS and RFS plots.
Fig. 4: Kaplan–Meier OS and RFS plots.

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Acknowledgements

We thank Claudia DeToma, Marine Largeau, Elodie Michel and Lauriane Chambolle for their work and implication at the Biological Resources centre and Tumour Bank Platform PRB-HEGP (BB-0033-00063).

Funding

This study was supported by a grant from the integrated site of cancer research ‘cancer research for personalised medicine’ (SIRIC CARPEM). AL received personal research grants from Fondation de la Recherche Médicale. We thank the Tumour Bank Platform (PRB-HEGP BB-0033-00063) for its support.

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Authors

Contributions

Conception or design: HB, SG and AL. Data collection: J-BL, FLP-B, AL, LG, CB, TD and AP. Data analysis: SG and AL. Redaction: AL, SG and HB. Final approval: SG, AD, TD, AP, GB, J-BL, J-BO, LG, CB, FLP-B, PL-P, AL and HB.

Corresponding author

Correspondence to Helene Blons.

Ethics declarations

Ethics approval and consent to participate

This study, conducted at the European Georges Pompidou hospital, was approved by CPP Ile de France 2 ethics committee (nos. 2012-08-09 and 2012-08-09 A1) and registered in clinical trial.gov (NCT03509779). Patients with NSCLC treated by surgery for curative intent signed informed consent for research and tumour tissues banking. Samples were stored frozen (−80 °C) at the Biological Resources centre and Tumour Bank Platform (PRB-HEGP BB-0033-00063).

Competing interests

AL reports grants from Fondation de la Recherche Médicale, during the conduct of the study. HB reports a grant from Site de la Recherche Intégrée sur le Cancer (SIRIC) CARPEM for this study.

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Garinet, S., Didelot, A., Denize, T. et al. Clinical assessment of the miR-34, miR-200, ZEB1 and SNAIL EMT regulation hub underlines the differential prognostic value of EMT miRs to drive mesenchymal transition and prognosis in resected NSCLC. Br J Cancer 125, 1544–1551 (2021). https://doi.org/10.1038/s41416-021-01568-7

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