Högskolan i Skövde

Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer-related mortality worldwide, with an especially high burden in Asian populations. Environmental exposures such as tobacco smoking and alcohol consumption are major risk factors that contribute to the onset and progression of lung cancer. Despite this, limited studies have explored the combined molecular impact of these exposures in Asian cohorts. This study aimed to investigate the transcriptomic alterations associated with tobacco and alcohol exposure in NSCLC patients of Asian descent using RNA sequencing data from The Cancer Genome Atlas (TCGA). A total of 38 male NSCLC patients of sAsian ethnicity were selected and stratified into two groups based on their exposure history, 27 with a history of both smoking and occasional alcohol use, and 11 with no such exposure. Differential gene expression analysis identified nine genes significantly dysregulated in the exposure group, including upregulation of SPAG11B, BMP7, and ZIC5, and downregulation of PAK3 and MTTP. Gene set enrichment analysis (GSEA) did not reveal any significantly enriched KEGG pathways at FDR < 0.05, indicating that while specific genes were affected, broader pathway-level changes were less pronounced. To uncover coordinated gene regulation, weighted gene co-expression network analysis (WGCNA) was performed, identifying 27 gene modules, of which seven were highly enriched for genes upregulated in the exposure group. Functional enrichment of three modules (darkturquoise, turquoise, and yellowgreen) revealed associations with cancer-related signaling (e.g., estrogensignaling, basal cell carcinoma), DNA damage response (e.g., mismatch repair, homologous recombination), xenobiotic metabolism (e.g., cytochrome P450), and immune-inflammatory pathways (e.g., NF-κB, IL-17, Toll-like receptor signaling). These findings suggest that combined tobacco and alcohol exposure is associated with distinct transcriptional changes in NSCLC, influencing pathways involved in oncogenesis, genomic instability, and immune dysregulation. However, limitations such as small sample size, selfreported exposure metrics, and lack of data on additional environmental pollutants and comorbidities should be addressed in future studies. Overall, this work contributes to a better understanding of how lifestyle exposures shape lung cancer biology in Asian populations.