Liquid biopsy in detecting early non-small cell lung cancer

Lung cancer screening programs, particularly in the UK, have shown a decrease in lung cancer-related deaths among individuals who underwent low-dose computed tomography (CT) screening. Researchers are now focusing on evaluating cell-free DNA through various methods to determine if pre-diagnostic mutations can be detected years before clinical diagnosis. This could help identify individuals at high risk of developing lung cancer. However, while this approach has successfully identified precursors of follicular lymphoma, the presence of occult lung preneoplasia in non-small-cell lung cancer still requires further investigation. The TRACERx consortium is conducting extensive research to comprehensively assess the detection and progression of non-small cell lung cancers (NSCLC). Liquid biopsy is being used in advanced stages of the disease to monitor disease progression, predict treatment response, and identify targetable driver oncogenic mutations and fusion genes. Intense research is also underway to identify numerous diagnostic gene signatures with high accuracy for early-stage lung cancer. However, a more focused clinical approach is needed, with a mechanistic focus on the key pathways of cancer development. Loss of liver kinase B1 (LKB1) function and deactivation due to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of tobacco-specific carcinogens, could potentially be traced and contribute to the development of new biomarkers. This testing could complement machine-learning approaches. The discovery of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in healthy lung tissues by TRACERx investigators may also lead to the development of novel diagnostic tools. Tumor protein 53 (TP53) loss should also be considered as a marker that could contribute to malignant transformation. Intercepting aggressive non-small-cell lung cancer is a pressing priority. In this review, we discuss our experience and explore other research on exosomes and plasma circular RNA as potential biomarkers. Circular RNAs, formed through non-sequential back-splicing of pre-mRNA transcripts, play a role in epithelial-mesenchymal transition, with many of them regulated by the RNA-binding protein Quaking. Platelet RNA has shown promise in detecting early and late-stage cancer. The extensive exploration of liquid biopsy aims to provide affordable methods for tracing circulating precursors of non-small-cell lung cancer, highlighting the importance of its mission.