Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization

Abel García Díaz; María José Moyano Rodríguez; María del Carmen Garrido Navas; Diego de Miguel Pérez; José Expósito Hernández; Bernardino Alcázar Navarrete; Francisco Ortuño Anderiz; David Landeira; Pedro José Romero Palacios; Adrián García Moreno; Jose A. Lorente; Javier L. López Hidalgo; Clara Isabel Bayarri Lara; María José Serrano Fernández

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Resectable Non-Small Cell Lung Cancer Heterogeneity and Recurrence Assessed by Tissue Next-Generation Sequencing Genotyping and Circulating Tumor Cell EZH2 Characterization

Abel Garcia Diaz ^[1] ; María José Moyano Rodríguez ^[3] ; María del Carmen Garrido Navas ^[1] ; Diego de Miguel Perez ^[4] ; Jose Expósito Hernández ^[2] ; Bernardino Alcázar Navarrete ^[5] ; Francisco Ortuño ^[1] ; David Landeira ^[1] ; Pedro J. Romero ^[1] ; Adrian Garcia Moreno ^[1] ; Jose A. Lorente ^[1] ; Javier Lopez Hidalgo ^[2] ; Clara Bayarri Lara ^[3] ; María José Serrano
1. [1] Universidad de Granada
  
  Universidad de Granada
  
  Granada, España
2. [2] Instituto de Investigación Biosanitaria de Granada
  
  Instituto de Investigación Biosanitaria de Granada
  
  Granada, España
3. [3] Department of Thoracic Surgery, Virgen de las Nieves University Hospital, Granada, Spain
4. [4] Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, NY, USA
5. [5] Department of Pneumology Virgen de las Nieves University Hospital, Granada, Spain
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Localización: Archivos de bronconeumología: Organo oficial de la Sociedad Española de Neumología y Cirugía Torácica SEPAR y la Asociación Latinoamericana de Tórax ( ALAT ), ISSN 0300-2896, Vol. 61, Nº. 3, 2025, págs. 156-165
Idioma: inglés
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Resumen
- Introduction Non-small cell lung cancer (NSCLC) is the most common type of lung neoplasm. Despite surgical resection, it has a high relapse rate, accounting for 30–55% of all cases. Next-generation sequencing (NGS) based on a customized gene panel and the analysis of circulating tumor cells (CTCs) can help identify heterogeneity, stratify high-risk patients, and guide treatment decisions. In this descriptive study involving a small prospective cohort, we focus on the phenotypic characterization of CTCs, particularly concerning EZH2 expression (a member of the Polycomb Repression Complex 2), as well as on the mutation profiles of the tissue using a customized gene panel and their association with poor outcomes in NSCLC.
  
  Methods Isolation and characterization of EZH2 on CTCs were evaluated before surgical resection (CTC1) and one month after surgery (CTC2) in resectable NSCLC patients. Targeted NGS was performed using a customized 50-gene panel on tissue samples from a subset of patients.
  
  Results 76 patients with resectable NSCLC were recruited. The top mutated genes in the cohort included TP53, FLT1, MUC5AC, EGFR, and NLRP3. Pair of genes that had mutually exclusive mutations was TP53-RIN3, and pairs of genes with co-occurring mutations were CD163-TLR4, FGF10-FOXP2, ADAMTSL3-FLT1, ADAMTSL3-MUC5AC and MUC5AC-NLRP3. CTCs decreased significantly between the two time points CTC1 and CTC2 (p<0.0001), and CTCs+ patients with high EZH2 expression had an 87% increased risk of death (p=0.018).
  
  Conclusions Integrating molecular profiling of tumors and CTC characterization can provide valuable insights into tumor heterogeneity and improve patient stratification for resectable NSCLC.