Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer, is a highly heterogeneous disease with significant variability in clinical outcomes and responses to treatment. Traditional classifications based on histopathological characteristics have proven insufficient for personalized therapy due to the complexity of molecular alterations within tumors. As precision medicine gains prominence, molecular stratification based on gene expression profiling has emerged as a powerful approach to better classify lung adenocarcinoma, enabling more targeted and effective therapeutic strategies.
Gene expression profiling allows for the identification of specific molecular signatures and genetic alterations that drive the progression and behavior of lung adenocarcinoma. Through high-throughput technologies such as RNA sequencing (RNA-seq) and microarray analysis, large-scale data on gene expression patterns can be generated, providing insights into the biological mechanisms underlying tumor heterogeneity. This molecular information enables stratification of LUAD into distinct subgroups with unique molecular profiles, each associated with specific clinical characteristics, prognosis, and therapeutic sensitivities. Understanding these molecular differences not only improves diagnostic accuracy but also offers the potential to identify novel therapeutic targets and biomarkers for patient selection.
Several molecular subtypes of lung adenocarcinoma have been identified through gene expression profiling, each characterized by distinct genomic alterations and signaling pathway dysregulations. One well-recognized subtype is driven by alterations in the epidermal growth factor receptor (EGFR) gene, which is found in a significant proportion of LUAD patients. EGFR mutations are particularly prevalent in non-smoking populations and are associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs), making them critical for treatment stratification. Similarly, other subtypes harbor mutations in genes such as KRAS, BRAF, and ALK, each of which has unique therapeutic implications.
In addition to driver mutations, gene expression profiling has identified several immune-related subtypes of lung adenocarcinoma, which differ in their tumor immune microenvironments and responses to immune checkpoint inhibitors (ICIs). Tumors with high expression of immune-related genes, often referred to as "hot" tumors, are characterized by active immune infiltration and are more likely to respond favorably to immunotherapy. Conversely, "cold" tumors, with low immune infiltration, may require combination therapies to enhance immune responsiveness.
A more comprehensive understanding of these subtypes through molecular stratification has significant implications for improving treatment outcomes. For instance, patients with EGFR-mutant or ALK-rearranged tumors benefit greatly from targeted therapies, which can lead to improved progression-free survival. Similarly, immune-related subtypes can guide the use of immunotherapy, ensuring that only patients most likely to benefit from these treatments receive them, while sparing others from potential toxicity and side effects.
