Evaluation of mutation profile detected by next generation sequencing in differentmetastatic organs in non-small cell lung cancer and its relationship with clinicopathological parameters

Non-Small Cell Lung Cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. Despite advances in treatments, survival rates are very low as the majority of patients are metastatic at diagnosis. In the molecular studies required for targeted therapies in NSCLC, there is heterogeneity between the primary tumor and its metastases, and mutations in the metastases are more common than in the primary. There are few studies in the literature examining the mutation profiles of lung cancer in different metastatic organs. This study aimed to identify somatic mutations detected by Next Generation Sequencing (NGS) in biopsies obtained from different metastatic organs of cases diagnosed with NSCLC and to evaluate their relationship with clinicopathological parameters. 128 cases diagnosed with NSCLC, whose biopsies obtained from different metastatic organs were evaluated by NGS in the Molecular Pathology laboratory of Aydın Adnan Menderes University Faculty of Medicine, Department of Medical Pathology, between 2019 and 2022, were included in the study. Age, gender, histopathological diagnoses, metastatic areas, smoking and mutation status, a total of 72 genes and 4149 primary analysis results in the panel of the NGS system were recorded. The mean age of the cases was 62.02 (Age range 31-89, SD: 9.87). There was male predominance (69%) and the majority of cases were in ADC morphology (91.4%). While 69 (53.9%) of the cases had a history of smoking, this rate was statistically significantly higher in males with 63.6% (p = 0.002). The smoking rate was higher in those with brain metastases (p=0.000). The most common lymph node metastasis was detected (39.8%), followed by brain (19.5%), bone (13.3%) and liver (11.7%). There was a significant correlation between the presence of mutation and liver (p=0.012), bone (p=0.002) and pleura (p=0.008) metastasis. The most frequently detected mutations were KRAS, NF1, TP53, EGFR, PTEN and BRAF, respectively. KRAS (p=0.044) mutations were more common in males, EGFR (p=0.000) in females, and KRAS (p=0.000) and TP53 (p=0.001) mutations were more common in smokers. NF1 in brain metastases (p=0.001) and BRAF mutation in liver (p=0.000) were statistically significant. XV The most common mutation associations are; NF1-TP53, PTEN-TP53, and NF1-PTEN. NF1-PTEN and NF1-TP53 were common in the brain, which is the most common metastatic organ, while KRAS-TP53 and NF1-TP53 were in the lymph node, and NF1- TP53 was in the bone. Our results have showed that a comprehensive evaluation of the detected mutations should be taken into account, especially in predicting organ tropism metastases of lung ADC, and that the mutational status of the tumor in the metastatic organs should also be taken into account in the follow-up and treatment of patients with these mutations. In the future, there will be new treatment agents to treat NSCLC that target mutations such as NF1, which are rarer but more frequently detected in metastases. Therefore, the discovery of agents targeting these and related pathways may prolong the survival of patients by reducing the risk of metastasis. Differences emerging between primary tumors and metastases will guide treatment strategies and the development of new drugs.