Gene expression and mutational profiling of NSCLC in relation to KRAS G12C.

The <italic>KRAS</italic> c.34G>T, p.(Gly12Cys) (G12C) variant is commonly found in non-small cell lung cancer (NSCLC) that is targeted with KRAS inhibitors. However, the success rate of this treatment is not satisfactory. To better understand NSCLC biology and identify potential biomarkers, it is important to analyze the relationship of <italic>KRAS</italic> variants with other oncogenesis-related genes. Therefore, the expression of 14 genes <italic>(ALK,BRAF,EGFR,FGFR1-3,KRAS,</italic> <italic>MET</italic>,<italic>NRG1</italic>, <italic>NTRK1-3</italic>, <italic>RET</italic>, and <italic>ROS1</italic>) was compared among 160 KRAS-positive and negative tumors (FFPE biopsies and surgically resected tissues), including 79% adenocarcinomas, 15% large cell lung cancer, and 6% not otherwise specified (NOS). The RNA-based next-generation sequencing method (NGS, Archer FusionPlex Lung) was used. Out of 160 samples, 58 (17.4%) had clinically significant <italic>KRAS</italic> variants, of which 95% were found in adenocarcinomas. The G12C was the most frequent among all KRAS-positive tumors (36%). KRAS-negative tumors had alterations: <italic>EGFR</italic> (n=13), <italic>BRAF</italic> (n=7), CD74::ROS1 (n=1), EML4::ALK (n=3), and METex14 skipping (n=6). The gene expression analysis revealed significantly higher median expression of the <italic>NTRK2</italic> (<italic>TrkB</italic>) in tumors with the G12C (p=0.016) and significantly lower median expression of the <italic>KRAS</italic> in tumors carrying the c.37G>T, p.(Gly13Cys) (p=0.011). This study provides new insights into the genomic characterization of KRAS-positive tumors, particularly those with G12C. Our analysis revealed higher levels of <italic>NTRK2</italic> in G12C-positive tumors, which could be associated with an unfavorable prognosis as NTRK2 signaling may contribute to metastasis and is associated with intratumoral hypoxia. Further research is necessary to confirm these observations. Project 3.9/2022