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

Co-occurring mutations in lung cancer can influence disease progression and treatment response. Understanding these patterns may refine prognostic stratification and therapeutic decisions.

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.

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.

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.