Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including, ,, , and, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional knockout allele to the mouse model, we further find that deletion dramatically promotes lung cancer progression. The tumor-promotive effect of knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the -knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.

Background and Objective To investigate the role of postoperative radiotherapy (PORT) in IIIA‐N2 non–small cell lung cancer (NSCLC) patients and subgroups which derived benefit from PORT. Methods A total of 576 patients with pathological IIIA‐N2 NSCLC, who underwent complete resection, were identified. Propensity score matching (PSM) methods were used to balance the patients' characteristics between two groups. Overall survival (OS) and relapse‐free survival (RFS) were compared between PORT and non‐PORT patients. Results On multivariable analysis, improved OS remained correlated with younger age, single N2 station involvement, less positive lymph nodes, and chemotherapy. After PSM, 121 PROT patients and 242 non‐PORT patients were matched. PORT was not associated improved patients' OS (P = 0.735) or RFS ( P = 0.483). For patients who underwent postoperative chemotherapy (POCT), PORT could improve OS in single N2 station involved patients (HR: 0.572, 95%CI: 0.312 to 1.05, P = 0.040). Patients with papillary predominant adenocarcinoma also benefited from PORT with an increase in OS (HR: 0.350, 95%CI: 0.126 to 0.972, P = 0.033). Conclusions For patients with completely resected IIIA‐N2 NSCLC, mediastinal lymph node metastasis and histologic subtypes could influence the effect of PORT. Single N2 station involvement and papillary predominant subtype were predictors of benefit from PORT.

PurposeTo determine the survival following segmentectomy versus lobectomy in elderly patients with early-stage non-small cell lung cancer (NSCLC).MethodsWe identified 12324 elderly (≥ 70 years) patients with stage I ≤ 3 cm NSCLC in the Surveillance, Epidemiology and End Results (SEER) database. Propensity score methods were used to balance baseline characteristics of patients undergoing segmentectomy or lobectomy. Overall survival (OS) and lung cancer-specific survival (LCSS) of patients treated with segmentectomy versus lobectomy were compared in Cox regression models after adjusting, stratifying or matching patients based on propensity scores.ResultsCox models adjusting, stratifying or matching propensity scores all showed that patients treated with segmentectomy had significantly worse OS and LCSS compared to lobectomy. Subgroup analysis of patients with tumors ≤ 2cm, aged ≥ 75 years, or had ≥ 7 lymph nodes examined also revealed survival advantage associated with lobectomy.ConclusionElder age alone could not justify the application of segmentectomy in early-stage lung cancer. Prospective randomized trials are warranted to validate our results.