Unique profile on the progress free survival and overall survival in patients with advanced non-small cell lung cancer in the Qujing area, Southwest China.

Background: China's southwestern region, Qujing, harbors a high incidence of non-small cell lung cancer (NSCLC) and related mortality. This study was designed to reveal the impact of an immune-related prognostic signature (IRPS) on advanced NSCLC in the Qujing. Methods: Tissue specimens from an independent cohort of 37 patients with advanced NSCLC were retrospectively evaluated to determine the relationship between the IRPS estimated by next-generation sequencing (NGS) and clinical outcome. To compare the IRPS in tissue and the clinical outcomes between Qujing and non-Qujing populations, we analyzed datasets of 23 patients with advanced NSCLC from The Cancer Genome Atlas (TCGA) database. In addition, an independent cohort (n=111) of blood specimens was retrospectively analyzed to determine the relationship between the IRPS and clinical outcome. Finally, we evaluated the utility of the blood IRPS in classifying 24 patients with advanced NSCLC who might benefit from immunotherapy. Results: In cohort 1, the Qujing population with tTMB-H (≥ 10 mutations/Mb) or KRAS mutations had shorter progression-free survival (PFS) (hazard ratio [HR] 0.37, 0.14 to 0.97, P = 0.04; HR 0.23, 0.08 to 0.66, P < 0.01) and overall survival (OS) (HR 0.05, 0.01 to 0.35, P < 0.01; HR 0.22, 0.07 to 0.66, P < 0.01). In cohort 2 of the Qujing population, bTMB-H (≥ 6 mutations per Mb) and KRAS mutations were related to PFS (HR 0.59, 0.36 to 0.99, P = 0.04; HR 0.50, 0.26 to 0.98, P = 0.04) and OS (HR 0.58, 0.35 to 0.96, P = 0.03; HR 0.48, 0.25 to 0.93, P = 0.03). Notably, the Qujing population with bTMB-H had superior PFS (HR 0.32, 0.09 to 1.09, P = 0.01), OS (HR 0.33, 0.10 to 1.13, P < 0.01) and objective response rates (ORRs) (83.3% vs. 14.3% vs. 20.0%, P <0.01) to immunotherapy than other populations. Conclusions: These findings show that tTMB, bTMB and KRAS mutations appear to be independent validated IRPSs that predict the clinical outcomes of Qujing populations with advanced NSCLC and that bTMB may be used as a reliable IRPS to predict the clinical benefit from anti-PD-1 therapies among populations from Qujing with advanced NSCLC.

Unique Profile of Driver Gene Mutations in Patients With Non-Small-Cell Lung Cancer in Qujing City, Yunnan Province, Southwest China.

OBJECTIVE: Qujing City, Yunnan Province, China, has a high incidence of lung cancer and related mortality. The etiology of NSCLC in Qujing area and distribution of associated molecular aberrations has not been fully elucidated. This study aimed to reveal the profile of driver gene mutations in patients with non-small-cell lung cancer (NSCLC) in Qujing and explore their relationships with clinicopathological characteristics. METHODS: In this study, the mutation profiles of NSCLC driver genes, including EGFR, ALK, ROS1, KRAS, BRAF, RET, MET, HER2, NRAS, and PIK3CA, were investigated in patients with NSCLC from Qujing and compared with those from other regions in Yunnan Province. The associations between molecular mutations and clinicopathological characteristics were further analyzed. RESULTS: A distinct profile of driver gene mutations was discovered in patients with NSCLC from Qujing. Interestingly, a higher proportion of EGFR compound mutations, including G719X + S768I (19.65% vs 3.38%, P < 0.0001) and G719X + L861Q (21.10% vs 2.82%, P < 0.0001), was observed in patients with NSCLC in Qujing compared with patients in non-Qujing area, besides significantly different distributions of EGFR (46.01% vs. 51.07%, P = 0.0125), ALK (3.17% vs. 6.97%, P = 0.0012), ROS1 (0.5% vs. 2.02%, P = 0.0113), and KRAS (23.02% vs. 7.85%, P < 0.0001). Further, EGFR compound mutations were more likely associated with the occupation of patients (living/working in rural areas, e.g., farmers). Moreover, KRAS G12C was the dominant subtype (51.11% vs 25.00%, P = 0.0275) among patients with NSCLC having KRAS mutations in Qujing. CONCLUSIONS: Patients with NSCLC in Qujing displayed a unique profile of driver gene mutations, especially a higher prevalence of EGFR compound mutations and dominant KRAS G12C subtype, in this study, indicating a peculiar etiology of NSCLC in Qujing. Therefore, a different paradigm of therapeutic strategy might need to be considered for patients with NSCLC in Qujing.

lncRNA DLEU2 modulates cell proliferation and invasion of non-small cell lung cancer by regulating miR-30c-5p/SOX9 axis.

Increasing evidence indicated that long noncoding RNAs (lncRNA) play critical roles in the progression of multiple cancers and that dysregulation of lncRNA promotes tumor progression. However, the function and underlying mechanism of lncRNA DLEU2 in biological behaviors of NSCLC cells are still largely unknown. Our studies confirmed that lncRNA DLEU2 was highly expressed in NSCLC tissues and cell lines, which was correlated with shorter overall survival in NSCLC patients. In vitro, knockdown of lncRNA DLEU2 inhibited proliferation, invasion, migration and induced apoptosis of both A549 and LLC cells; In vivo, it suppressed tumor growth and metastasis. lncRNA DLEU2 directly interacted with miR-30c-5p, which further targeted SOX9 and exerted oncogenic functions in NSCLC. Mechanistically, overexpression of lncRNA DLEU2 exhibits tumorigenic effects through downregulating the inhibitory effect of miR-30c-5p on SOX9 expression. In conclusion, Our finding confirmed that lncRNA DLEU2 as a novel oncogenic in NSCLC, which provide a potential novel diagnostic and therapeutic target for NSCLC.

Epidermal growth factor receptor T790M mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China.

To explore the effect of epidermal growth factor receptor (EGFR) T790M mutation status on non-small cell lung cancer (NSCLC) in Yunnan province of southwestern China. First, this study used the super amplification refractory mutation system (Super ARMS) polymerase chain reaction (PCR) and Droplet Digital PCR (dd PCR) to evaluate the T790M gene mutation, in plasmatic ctDNA samples from 212 cases of NSCLC. The association between T790M mutations and clinical parameters were further explored. Next, to investigate the mechanism of drug resistance that resulted from T790M mutation, subgroup analyses according to duration of medicine (EGFR-TKIs) were carried out. Finally, we also evaluate the effectiveness of blood-based circulating tumor DNA (ctDNA) on detecting the T790M mutation by calculating Super ARMS's detection efficiency. We found that the T790M mutation rate was 8.4% (18/212) in overall patients. The T790M mutation was more frequent in patients with brain metastasis 30.0% (12/40) (p < 0.01). We found that post-TKI samples 42.8% (15/35) were associated with a higher T790M mutation rate (p < 0.01). Subgroup analysis showed that the duration of TKI therapy for 6 to 10 months 66.6% (8/12) (p < 0.01) and >10 months 75.0% (9/12) (p < 0.01) were also associated with a higher T790M mutation rate. Super ARMS's sensitivity, specificity, PPV, NPV, and accuracy were 100.0%, 99.4%, 94.7%, 100.0%, and 99.5% respectively. Generally, the EGFR-T790M mutation was more common in NSCLC patients with brain metastasis and those who received TKI therapy for more than 6 months. Moreover, Super ARMS is a sensitive, efficient, and practical clinic method for dynamically monitoring T790M mutation status and effectively guiding clinic treatment.

[Establishment of Orthotopic Xuanwei lung cancer SCID mouse model and analysis of biological properties].

BACKGROUND: The incidence of Xuanwei lung cancer ranks first in China, and its pathogenesis requires in-depth investigation. This study aims to establish an orthotopic Xuanwei lung cancer severe combined immunodeficiency (SCID) mouse model and to provide a basic experimental platform for further study. METHODS: The Xuanwei lung cancer cell line XWLC-05 was inoculated into the lung tissue of SCID mice in high and low doses. The tumor formation rates, tumor characteristics, spontaneous metastases, and survival times of the mice were observed, taking a subcutaneously transplanted tumor as control. RESULTS: The tumor formation rates of the orthotopic transplantation of lung cancer cells in high and low doses were 81% and 83%, respectively, among which mice in the high-dose group appeared cachectic on day 13. Extensive invasion and adhesion were observed in the contralateral lung and thoracic cavity, but no distant metastasis was exhibited. Mice with low-dose cells in the orthotopic transplantation group appeared cachectic and distant metastasis occurred on day 25. The tumor formation rates in the subcutaneous inoculation group by the high and low doses of cells were 100% and 94.5%, respectively, and no distant metastasis was observed. The rate of metastasis within the orthotopic transplantation group and between the orthotopic and subcutaneous inoculation groups showed a significant difference (P<0.05). A significant difference was indicated by the survival rate within and between the groups (P<0.001). CONCLUSIONS: We successfully established an orthotopic XWLC SCID mouse model, which lays the foundation for a more in-depth study.