Genomic alterations and co-mutation patterns in advanced NSCLC: a real-world DNA-based NGS study in a large Turkish cohort

Abstract

The increasing use of next-generation sequencing (NGS) has revealed substantial molecular heterogeneity in advanced non-small cell lung cancer (NSCLC), yet real-world co-mutation patterns remain incompletely characterized. We aimed to investigate the genomic landscape and clinically relevant co-alteration patterns in a large real-world cohort of patients with advanced NSCLC from Türkiye. A total of 1500 patients with advanced NSCLC were retrospectively analyzed. Targeted DNA-based NGS was performed via QIAGEN GeneReader panels on formalin-fixed, paraffin-embedded tissue and plasma samples. Single nucleotide variants, insertions/deletions, and copy number variations were evaluated, and associations with clinicopathological features were analyzed. The most frequent genomic alterations were detected in EGFR (23.7%) and KRAS (22.5%), followed by MET , STK11 , PIK3CA , and FGFR1 . EGFR alterations and ERBB2 mutations were more common in females, whereas KRAS , FGFR1 , and MET alterations were more common in males. The predominant EGFR mutations were exon 19 deletions and L858R substitutions, whereas KRAS G12C was the most common KRAS variant. EGFR amplification was detected in 12.1% of the patients and frequently co-occurred with EGFR mutations. EGFR and KRAS alterations demonstrated a largely mutually exclusive pattern, whereas KRAS commonly co-occurred with STK11 and PIK3CA alterations. Distinct genomic profiles were also observed across histological subtypes. This large-scale real-world study demonstrates the heterogeneous molecular landscape of advanced NSCLC and identifies clinically relevant co-alteration patterns involving EGFR , KRAS , STK11 , MET , and PIK3CA . These findings highlight the value of DNA-based NGS profiling for characterizing the genomic landscape and recurrent co-alteration patterns in advanced NSCLC and may inform molecular assessment in routine clinical practice.