Co-mutation patterns and survival associations in lung cancer: a comparative analysis of Swedish and global cohorts

BACKGROUND AND PURPOSE: Co-occurring mutations in lung cancer can influence disease progression and treatment response. Understanding these patterns may refine prognostic stratification and therapeutic decisions. PATIENTS/MATERIALS AND METHODS: We analysed targeted sequencing data from 528 North Swedish non-small cell lung cancer (NSCLC) patients, validating findings in 2,239 global patients. Co-mutation enrichment was assessed using the Fisher's exact test with odds ratios, and survival associations were evaluated using Kaplan-Meier/log-rank analyses and Cox models. RESULTS: The North Sweden cohort showed non-random co-mutation patterns shaped by pathway dependencies. The combination of Kirsten rat sarcoma virus oncogene homolog (KRAS) and STK11 co-mutation was significantly enriched in both North Sweden (p = 4.7 × 10-4) and globally (p = 2.5 × 10-22), with North Sweden co-mutants showing significantly worse survival compared with KRAS-only cases (p = 0.037). Epidermal growth factor receptor (EGFR)+phosphate and tensin homolog (PTEN) co-mutation was significantly associated with poorer survival in both cohorts (North Sweden: p = 0.013; World: p = 0.0013). EGFR+TP53 co-mutation trended towards poorer survival compared with EGFR alone, reaching significance globally (p = 1.4 × 10-5). Adenomatous polyposis coli (APC) and PTEN were positively enriched in North Sweden (p = 0.018), and co-mutants had worse survival than APC-only cases (p = 0.029), a pattern mirrored globally. KRAS+TP53 was a frequent co-mutation but not prognostically significant. KRAS and EGFR were strongly mutually exclusive in both cohorts. INTERPRETATION: Pathway-level co-mutation interactions, rather than individual mutation burden, drive survival heterogeneity in lung cancer. Specific co-mutations, such as KRAS+STK11 and APC+PTEN, are enriched and linked to worse survival, supporting the clinical relevance of co-mutation analysis in NSCLC.