The Genomic Landscape of Romanian Non-Small Cell Lung Cancer Patients: The Insights from Routine NGS Testing with the Oncomine™ Dx Express Test at the PATHOS Molecular Pathology Laboratory

<b>Background:</b> Comprehensive molecular profiling is essential for precision oncology in non-small cell lung cancer (NSCLC). However, genomic data from Eastern European populations, including Romania, remain limited. <b>Methods:</b> We analyzed 398 consecutive NSCLC cases tested at the PATHOS Molecular Pathology Laboratory (Cluj-Napoca, Romania) between April 2024 and February 2025 using the Ion Torrent™ Genexus™ System and the Oncomine™ Dx Express Test, which evaluates SNVs/indels in 46 genes, fusions in 23 genes, and CNVs in 19 genes from FFPE samples. <b>Results</b>: The cohort was predominantly male (66%) with a median age of 67 years. Adenocarcinoma represented 70% of cases with known histology. Genomic profiling revealed a high frequency of actionable alterations. <i>KRAS</i> mutations were the most common (29.1%), with p.G12C detected in 10.3% of all the cases. <i>EGFR</i> mutations were present in 14.3% of patients, mostly exon 19 deletions and L858R substitutions. <i>BRAF</i> alterations (5.3%) included both V600E and non-V600E variants. RET alterations were detected as eight missense mutations, two canonical fusions (<i>KIF5B</i>-<i>RET</i>, <i>CCDC6</i>-<i>RET</i>), one amplification, and three transcript imbalances. <i>EML4-ALK</i> fusions (1.77%), <i>ERBB2</i> mutations/amplifications (3.0%), and <i>FGFR1/FGFR3</i> amplifications were also observed. <b>Conclusions</b>: This study provides the first large-scale molecular snapshot of NSCLC in Romania. While the overall genomic profiles align with Western populations, the higher frequency of KRAS p.G12C and <i>FGFR</i> amplifications highlights the value of region-specific data to support targeted therapies in Eastern Europe.