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  • In NSCLCs increasing numbers of studies have focused on


    In NSCLCs, increasing numbers of studies have focused on evaluating the association between lymph node metastasis, impact factors and drainage pattern [20,21]. There have been no studies specifically designed to evaluate which genotype of NSCLC is more likely to have lymph node metastasis. Therefore, an emerging issue concerning the lymph node metastasis in NSCLC is the identification of driver mutation markers for predicting patients who will most likely develop lymph node metastasis. This study aimed to determine the incidence and distribution of lymph node metastasis according to different driver mutations in stage T1 NSCLC.
    Discussion Mutations of driver FLAG tag Peptide contribute to oncogenesis and progression of tumor. In particular, mutation status of early stage NSCLC may help identify groups of patients with small size tumors at high risk for lymph node metastasis that may receive the most benefit from adjuvant therapy. Genetic factors associated with an increased risk of lymph node metastasis are not certain. Consistent with our results, Li et al. [27] performed a retrospective study including 675 patients with early stage lung adenocarcinomas, the results suggested that ALK rearrangement was more common in those with lymph node metastasis compared with EGFR mutations, while no significance difference was observed between EGFR, KRAS and wild type mutations in terms of node metastasis. Another study of patients with completely resected stage IA lung adenocarcinoma by Shin et al. [28] reported that ALK rearrangement was associated with more regional lymph node metastasis and unfavorable disease-free survival compared to ALK-negative patients. In a prevalence analysis [29] of ROS1 fusion, ROS1 status was significantly correlated with lymph node metastasis and ROS1 positive was found higher in patients at advanced node stages. Similarly, another study [30] reported that patients harboring RET fusion gene tended to present with more N2 stage (54.5%) in small tumors (≤3 cm), significantly higher than the other lung adenocarcinomas without RET fusion (22.6%). In our study, we included more patients and have more target genes involved. Only patients with pathological T1 NSCLC were included, because a larger tumor is correlated with a higher risk for the development of lymph node metastasis. A targeted next-generation sequencing method was used for this mutational analysis in 1052 NSCLC patients. The frequencies of driver mutations in our study were similar to those reported by multinational epidemiologic studies [24,[31], [32], [33], [34]] in NSCLC among East Asian populations, which ensured the reliability of our study. The change in the frequency of driver mutations from node negative to node positive disease indicated that some oncogenic mutations occur during the carcinogenetic process from less aggressive to more aggressive tumors. The molecular characteristics reported by other studies [[35], [36], [37], [38]] also support the multistep tumorigenesis and progression in lung cancers. The highest-ranking node metastatic rate of different genotypes was ROS1 rearrangement (72.8%) in our study. Our study showed that the lymph node metastasis exhibited mainly in fusion mutations. When further stratified by age, gender and smoking history, patients with fusion mutations still showed a higher node-metastatic rate compared with other mutations. The presence of fusion genes was a statistically significant predictor of lymph node metastasis. Tumor-associated lymph node involvement is a complicated process, different genotypes present with different genomic features, lymph node metastasis may be driven by gene mutations as well as signaling pathways activated by gene alterations. Previous studies [30,[39], [40], [41], [42]] also have reported that NSCLC harboring ROS1, ALK or RET fusions share some clinicopathological characteristics, such as young age of onset and light / never smoking history, suggesting that similar routes of oncogenesis might exist in these fusion subtypes of NSCLC. Tumors activated by fusion mutations tend to have lower mutational burden and less neoantigens [43], which may lead to the disorders of immune recognition against cancer and promote the metastasis of lymphatic drainage through immune escape.