Multiplexed Molecular Endophenotypes Help Identify Hub Genes in Non-Small Cell Lung Cancer: Unlocking Next-Generation Cancer Phenomics

Next-generation cancer phenomics by deployment of multiple molecular endophenotypes coupled with high-throughput analyses of gene expression offer veritable opportunities for triangulation of discovery findings in non-small cell lung cancer (NSCLC) research. This study reports differentially expressed genes in NSCLC using publicly available datasets (GSE18842 and GSE229253), uncovering 130 common genes that may potentially represent crucial molecular signatures of NSCLC. Additionally, network analyses by GeneMANIA and STRING revealed significant coexpression and interaction patterns among these genes, with four notable hub genes— GRK5, CAV1 , PPARG , and CXCR2 —identified as pivotal in NSCLC progression. Validation of these hub genes indicated their consistent downregulation in tumor tissues compared to normal counterparts. Gene expression across the endophenotypes representing pathological stages revealed distinct downregulation trends, emphasizing their putative roles as biomarkers for cancer progression. Moreover, three miRNAs (hsa-miR-429, hsa-miR-335-5p, and hsa-miR-126-3p) showed strong associations with these hub genes, while SREBF1 emerged as a relevant transcription factor. Pathway enrichment analysis identified the chemokine signaling pathway as significantly associated with these genes, highlighting its role in tumor progression and immune evasion. Cell-type enrichment analysis indicated that endothelial cells may play a significant role in NSCLC pathogenesis. Finally, survival analysis demonstrated that GRK5 is a potential oncogenic marker, whereas CAV1 may have a protective effect. These findings collectively underscore the critical molecular interactions in NSCLC and suggest novel paths for translational research, targeted therapies, and prognostic markers in clinical settings. They also attest to the promises of next-generation cancer phenomics using multiple endophenotypes for discovery and triangulation of novel findings.