Prognostic value of KRAS G12V mutation in lung adenocarcinoma stratified by stages and radiological features.

OBJECTIVE: KRAS G12V is one of the most common KRAS mutation variants in lung adenocarcinoma (LUAD), and yet its prognostic value is still unrevealed. In this study, we investigated the clinicopathologic characteristics and prognostic value of the KRAS G12V mutation in LUAD. METHODS: Data of 3829 patients who underwent LUAD resection between 2008 and 2020 were collected. Mutations were classified as wild-type, G12V, or non-G12V. The clinicopathologic characteristics, postoperative outcomes, and recurrence pattern were analyzed among groups. RESULTS: In total, 3554 patients were wild-type and 275 patients harbored a KRAS mutation: 60 patients with G12V (22.2%) and 215 patients with non-G12V (77.8%). The KRAS G12V mutation was more frequent in male patients, older patients (≥60 years), former/current smokers, those patients with radiologic solid nodules, and those with highly invasive histologic subtypes. Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. Multivariate analysis demonstrated that the KRAS G12V mutation was an independent prognostic factor in stage Ⅰ tumors, whereas the KRAS non-G12V mutation was not. KRAS G12V was associated with early recurrence and locoregional recurrence. CONCLUSIONS: The KRAS G12V mutation was associated with aggressive clinical-pathologic phenotype and early recurrence. To note, this mutation exhibited a significantly worse prognosis in patients with part-solid and stage Ⅰ lung adenocarcinoma. Meanwhile, the prognostic significance of KRAS G12C and G12V variants was comparable.

RBM10 Loss Promotes EGFR-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition.

In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD data sets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. RBM10 loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, RBM10 deficiency conferred high sensitivity to spliceosome inhibition in EGFR-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD. SIGNIFICANCE: Loss of the splicing factor RBM10 is mutually exclusive with p53 mutations, promotes tumorigenesis, and enhances the efficacy of spliceosome inhibition in EGFR-driven lung cancer.

RNA splicing alterations in lung cancer pathogenesis and therapy.

RNA splicing alterations are widespread and play critical roles in cancer pathogenesis and therapy. Lung cancer is highly heterogeneous and causes the most cancer-related deaths worldwide. Large-scale multi-omics studies have not only characterized the mutational landscapes but also discovered a plethora of transcriptional and post-transcriptional changes in lung cancer. Such resources have greatly facilitated the development of new diagnostic markers and therapeutic options over the past two decades. Intriguingly, altered RNA splicing has emerged as an important molecular feature and therapeutic target of lung cancer. In this review, we provide a brief overview of splicing dysregulation in lung cancer and summarize the recent progress on key splicing events and splicing factors that contribute to lung cancer pathogenesis. Moreover, we describe the general strategies targeting splicing alterations in lung cancer and highlight the potential of combining splicing modulation with currently approved therapies to combat this deadly disease. This review provides new mechanistic and therapeutic insights into splicing dysregulation in cancer.

Increased Tumor Intrinsic Growth Potential and Decreased Immune Function Orchestrate the Progression of Lung Adenocarcinoma.

Background: The overall 5-year survival of lung cancer was reported to be only ~15%, with lung adenocarcinoma (LUAD) as the main pathological subtype. Before developing into invasive stages, LUAD undergoes pre-invasive stages of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), where surgical resection gives an excellent 5-year survival rate. Given the dramatic decline of prognosis from pre-invasive to invasive stages, a deeper understanding of key molecular changes driving the progression of LUAD is highly needed. Methods: In this study, we performed whole-exome sequencing and RNA sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens, and their adjacent paired normal tissues. Survival data were obtained by follow-up after surgery. Key molecular events were found by comparing the gene expression profiles of tumors with different stages. Finally, to measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment, a tumor progressive (TP) index was developed to predict tumor progression and patients' survival outcome and validated by external datasets. Results: As tumors progressed to more invasive stages, they acquired higher growth potential, mutational frequency of tumor suppressor genes, somatic copy number alterations, and tumor mutation burden, along with suppressed immune function. To better predict tumor progression and patients' outcome, TP index were built to measure the imbalance between tumor intrinsic growth potential and immune microenvironment. Patients with a higher TP index had significantly worse recurrence-free survival [Hazard ratio (HR), 10.47; 95% CI, 3.21-34.14; p < 0.0001] and overall survival (OS) [Hazard ratio (HR), 4.83e8; 95% CI, 0-Inf; p = 0.0013]. We used The Cancer Genome Atlas (TCGA)-LUAD dataset for validation and found that patients with a higher TP index had significantly worse OS (HR, 1.10; 95% CI, 0.83-1.45; p = 0.048), demonstrating the prognostic value of the TP index for patients with LUAD. Conclusions: The imbalance of tumor intrinsic growth potential and immune function orchestrate the progression of LUAD, which can be measured by TP index. Our study provided new insights into predicting survival of patients with LUAD and new target discovery for LUAD through assessing the imbalance between tumor intrinsic growth potential and immune function.

NRAS expression is associated with prognosis and tumor immune microenvironment in lung adenocarcinoma.

PURPOSE: NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. METHODS: We obtained the transcriptome profiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then, we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers. RESULTS: Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. CONCLUSIONS: To conclude, we found NRAS is a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.

Uniportal versus multiportal video-assisted thoracoscopic anatomical resection for NSCLC: a meta-analysis.

BACKGROUND: Uniportal video-assisted thoracoscopic surgery (U-VATS) has recently emerged as an alternative procedure for non-small cell lung cancer (NSCLC); however, whether U-VATS has advantages over multiportal VATS (M-VATS) remains unknown. METHODS: We performed a systematic review of two databases (Pubmed and Web of Science) to search comparative studies of U-VATS and M-VATS anatomical pulmonary resection for NSCLC. Operative time, blood loss, number of resected lymph nodes, drainage duration, length of postoperative stay, pain in postoperative day 1(POD1) and conversion rates were retrieved to estimate the comparison of outcomes. A subgroup analysis stratified by study type (propensity-matched analysis and randomized-controlled trial versus non-propensity matched analysis) was performed. RESULT: A total of 20 studies with 4142 patients were included in this meta-analysis. U-VATS was performed on 1869 patients, whereas the other 2173 patients underwent M-VATS. This meta-analysis showed that there was no significant difference in operative time (U-VATS: 146.48 ± 55.07 min versus M-VATS: 171.70 ± 79.40 min, P = 0.81), blood loss (74.49 ± 109.03 mL versus 95.48 ± 133.67 mL, P = 0.18), resected lymph nodes (17.28 ± 9.46 versus 18.31 ± 10.17, P = 0.62), conversion rate (6.18% versus 4.34%, P = 0.14), drainage duration (3.90 ± 2.94 days versus 4.44 ± 3.12 days, p = 0.09), length of postoperative stay (6.16 ± 4.40 days versus 6.45 ± 4.80 days, P = 0.22), and pain in POD1 (3.94 ± 1.68 versus 3.59 ± 2.76, p = 0.07). Subgroup analysis showed the value of PSM and RCT group consistency with overall value. CONCLUSION: This up-to-date meta-analysis shows that the perioperative outcomes of U-VATS and M-VATS anatomical pulmonary resection are equivalent. In addition, the differences in long-term outcomes of these two approaches are still unclear. Thoracic surgeons should pay more emphasize on providing high-quality and personalized surgical care for patients, to improve the survival ultimately.

Measuring the preference towards patient-centred communication with the Chinese-revised Patient-Practitioner Orientation Scale: a cross-sectional study among physicians and patients in clinical settings in Shanghai, China.

OBJECTIVES: To adapt the Patient-Practitioner Orientation Scale (PPOS), to a Chinese context, and explore the preference towards patient-centred communication among physicians and patients with the Chinese-revised Patient-Practitioner Orientation Scale (CR-PPOS). DESIGN: A cross-sectional questionnaire-based study. SETTING: Clinical settings from eight medical units, including four community hospitals and four general hospitals, in Shanghai, China. PARTICIPANTS: 1018 participants, including 187 physicians and 831 patients, completed this study in two successive stages. OUTCOME MEASUREMENTS: Psychometric properties of the CR-PPOS and participants' score on the CR-PPOS. RESULTS: Compared with the original PPOS, the 11-item CR-PPOS obtained better psychometric indices. Physicians and patients scored differently on both the total CR-PPOS and its two subscales. Compared with physicians, the scores of patients were more influenced by their personal characteristics, such as age and education. CONCLUSIONS: The CR-PPOS is a better instrument in a Chinese context than the original translated version. The divergence in the extent to which patient-centred communication is preferred among Chinese physicians and patients should be noted. Adapting physicians' communication strategy to patients' preferences based on their personal characteristics can be a viable approach towards improving clinical efficiency.