Identification of nine mutant genes and establishment of three prediction models of organ tropism metastases of non-small cell lung cancer.

BACKGROUND: Most Non-small cell lung cancer (NSCLC) patients tend to have metastases at the initial diagnosis. However, limited knowledge has been established regarding which factors, are associated with its metastases. This study aims to identify more biomarkers associated with its organ tropism metastasis and to establish models for prediction of its metastatic organs. METHODS: We performed targeted next-generation sequencing (NGS) to detect genes related to lung cancer in 272 patients with primary advanced NSCLC from Northeast China. We adopted Fisher test, multivariate logistic regression analysis to identify metastasis-related gene mutations and to establish prediction models. RESULTS: Mutations of EGFR (p = 0.0003, OR = 2.554) (especially EGFR L858R [p = 0.02, OR = 2.009]), ATM (p = 0.008, OR = 11.032), and JAK2 (p = 0.009, OR = Inf) were positively and of TP53 exon4mut (p = 0.001, OR = 0.173) was negatively correlated with lung metastasis, and those of CSF1R (p = 0.01, OR = Inf), KIT (p = 0.03, OR = 4.746), MYC (p = 0.05, OR = 7.938), and ERBB2 (p = 0.02, OR = 2.666) were positively correlated with pleural dissemination; those of TP53 (p = 0.01, OR = 0.417) was negatively, while of SMAD4 (p = 0.03, OR = 4.957) was positively correlated with brain metastasis of NSCLC. Additionally, smoking history (p = 0.004, OR = 0.004) was negatively correlated with pleural dissemination of NSCLC. Furthermore, models for prediction of lung metastasis (AUC = 0.706), pleural dissemination (AUC = 0.651), and brane metastasis (AUC = 0.629) were established. CONCLUSION: Taken together, this study revealed nine mutant genes and smoking history associated with organ tropism metastases of NSCLC and provided three models for the prediction of metastatic organs. This study enables us to predict the organs to which non-small cell lung cancer metastasizes before it does develop.

Molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and potential treatment strategies.

BACKGROUND: Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non-small-cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. METHODS: A total of 17,978 Chinese patients with NSCLC who underwent next -generation sequencing (NGS) testing were retrospectively reviewed. RESULTS: We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active-site mutations, including IDH1R100 , IDH1R132 , IDH2R140 , and IDH2R172 , were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active-site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p < 0.001) or BRAF (p. V600E, 6.5% vs. 1.0%, p < 0.001), but significantly lower coalterations in activating EGFR (e18-e20, 22.7 vs. 37.9%, p < 0.001) than IDH wild-type patients. Furthermore, we found that active-site IDH mutations were correlated with a short PFS (2-5.6 months) and short OS (2-9.5 months), which may arise as a resistance mechanism against common targeted drugs. In vitro, we experimentally observed that the combination of an IDH inhibitor and EGFR TKI could better inhibit lung cancer cell proliferation than an EGFR TKI alone. CONCLUSIONS: Taken together, this study reveals the molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and provides a theoretical basis for IDH-directed treatment. The potential of IDH mutations as response markers for targeted therapy warrants further investigation.