The EML4-ALK fusion gene has been recently identified in a small subset of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of the EML4-ALK fusion gene in Chinese patients with NSCLC are poorly understood. Here, we report on the prevalence of EML4-ALK, EGFR status and KRAS mutations in 208 Chinese patients with NSCLC. EGFR mutations were found in 24.5% (51/208) of patients. In concordance with previous reports, these mutations were identified at high frequencies in females (47.5% vs 15.0% in males; P<0.05); never-smokers (42.3% vs 13.9% in smokers; P<0.05), and adenocarcinoma patients (44.2% vs 8.0% in non-adenocarcinoma patients; P<0.05). There were only 2.88% (6/208) patients with KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208), including 4 cases with variant 3 (57.1%), 2 with variant 1, and 1 with variant 2. All positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female, non-smoking adenocarcinoma patients was as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among the EML4-ALK positive patients. Pathological analysis showed no difference between solid signet-ring cell pattern (4/7) and mucinous cribriform pattern (3/7) in ALK-positive patients. Immunostaining showed intratumor heterogeneity of ALK rearrangement in primary carcinomas and 50% (3/6) of metastatic tumors with ALK-negative staining. Meta-analysis demonstrated that EML4-ALK translocation occurred in 4.84% (125/2580) of unselected patients with NSCLC, and was also predominant in non-smoking patients with adenocarcinoma. Taken together, EML4-ALK translocations were infrequent in the entire NSCLC patient population, but were frequent in the NSCLC subgroup of female, non-smoker, adenocarcinoma patients. There was intratumor heterogeneity of ALK rearrangement in primary carcinomas and at metastatic sites.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. However, science has not yet been able to substantially improve the prognosis of lung cancer patients. Accumulating evidence suggests that microRNAs (miRNAs) are key players in the regulation of tumor development and metastasis. Expression of six miRNAs previously shown to play roles in tumor development (miR-146b-5p, miR-128b, miR-21, miR-221, miR-34a, and Let-7a) in other tumor types was examined using real-time RT-PCR in 78 specimens of NSCLC. The results revealed that patients with low expression of miR-146b-5p had significant shorter median and mean survival time than those with high miR-146b-5p expression (33.00 and 30.44 months versus 42.0 and 36.90 months, respectively; log-rank test P=0.048), thus low miR-146b-5p expression level was associated with poor prognosis in NSCLC patients. Univariate Cox hazard regression analysis demonstrated that miR-146b-5p expression levels tended to be a significant prognostic indicator of NSCLC (adjusted hazard ratio=0.482, 95% CI: 1.409- 29.593, P=0.016). Multivariate Cox proportional hazard regression analysis showed that miR-146b-5p expression levels were an independent prognostic factor for NSCLC patients (hazard ratio=0.259, 95% CI: 0.083-0.809, P=0.020). Furthermore, the effects of miR-146b-5p and miR-146b-3p on NSCLC cell growth and invasion in vitro were investigated. Our findings demonstrate that ectopic expression of miR-146b-5p suppressed cell proliferation, clonogenicity, migration/ invasion and also induced G1 arrest in vitro, but did not induce cell apoptosis; whereas enforced expression of miR-146b-3p did not have a significant effect on cell growth and metastasis. Further experiments indicated that miR-146b-5p could reduce mRNA levels of MMP16 and TRAF6 in vitro and was negatively related to the expression of TRAF6 in human NSCLC tissues. In a mouse model, Ago-miR-146b-5p could significantly inhibit the growth of lung cancer xenografts in nude mice. In conclusion, our findings demonstrate that miR-146b-5p functions as a suppressor miRNA and prognosis predictor in NSCLC.
A novel class of HIFU and redox dual responsive polymer with a disulfide bond weak linkage is developed. The novel modality of HIFU and redox triggered release allows for the fine-tuning of the release kinetics of the encapsulants from the micelles in a remote and controlled way.
Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings may help guide the design of treatment regimens in SCLC.
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