Gene amplification in the premalignant stages of non-small cell lung cancer development

Lung cancer remains the leading cause of cancer-related mortality worldwide. Over the past decade, major advances in targeted and immune-based therapies have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC). However, further reducing mortality will require shifting intervention to the earliest, most curable stages of disease. Somatic copy-number alterations (SCNAs) are established drivers of NSCLC, and recent publications add to the growing evidence that gene amplifications, among the most frequent SCNAs in lung cancer, emerge early in carcinogenesis, including in premalignant and minimally invasive lesions. These early events can confer growth advantages that support clonal expansion, increase genomic instability, and propel progression toward invasive malignancy long before clinical diagnosis. Consequently, early gene amplifications represent a promising class of biomarkers for identifying high-risk lesions, refining risk stratification in screening settings, and exposing vulnerabilities amenable to early intervention. In this article, we synthesize current evidence on early amplification events in lung adenocarcinoma and lung squamous cell carcinoma, discuss their translational relevance for early detection and intervention, and outline key challenges and priorities for future research.