Mutational and Transcriptional Characterization Establishes Prognostic Models for Resectable Lung Squamous Cell Carcinoma.

Background: The prognosis of non-small cell lung cancer (NSCLC) patients has been comprehensively studied. However, the prognosis of resectable (stage I-IIIA) lung squamous cell carcinoma (LUSC) has not been thoroughly investigated at genomic and transcriptional levels. Methods: Data of genomic alterations and transcriptional-level changes of 355 stage I-IIIA LUSC patients were downloaded from The Cancer Genome Atlas (TCGA) database, together with the clinicopathological information (training cohort). A validation cohort of 91 patients was retrospectively recruited. Data were analyzed and figures were plotted using the R software. Results: Training cohort was established with 355 patients. TP53 (78%), TTN (68%), CSMD3 (39%), MUT16 (36%) and RYR2 (36%) were genes with the highest mutational frequency. BRINP3, COL11A1, GRIN2B, MUC5B, NLRP3 and TENM3 exhibited significant higher mutational frequency in stage III (P < 0.05). Patients with stage III also exhibited significantly higher tumor mutational burden (TMB) than those with stage I (P < 0.01). The mutational status of 10 genes were found to have significant stratification on patient prognosis. TMB at threshold of 25 percentile (TMB = 2.39 muts/Mb) also significantly stratified the patient prognosis (P = 0.0003). Univariate and multivariate analyses revealed TTN, ADGRB3, MYH7 and MYH15 mutational status and TMB as independent risk factors. Further analysis of transcriptional profile revealed many significantly up- and down-regulated genes, and multivariate analysis found the transcriptional levels of seven genes as independent risk factors. Significant factors from the multivariate analyses were used to establish a Nomogram model to quantify the risk in prognosis of individual LUSC patients. The model was validated with a cohort containing 91 patients, which showed good predicting efficacy and consistency. Conclusion: The influencing factors of prognosis of stage I-III LUSC patients have been revealed. Risk factors including gender, T stage, cancer location, and the mutational and transcriptional status of several genes were used to establish a Nomogram model to assess the patient prognosis. Subsequent validation proved its effectiveness.

Various Subtypes of EGFR Mutations in Patients With NSCLC Define Genetic, Immunologic Diversity and Possess Different Prognostic Biomarkers.

Based on data analysis of 9649 Chinese primary NSCLC patients, we calculated the exact proportion of EGFR subtypes in NSCLC and evaluated the TMB level, PD-L1 expression level and tumor immune microenvironment among different EGFR mutation subtypes. Postoperative follow-up data for 98 patients were collected and analyzed. The results showed that several uncommon EGFR mutation subtypes have a higher proportion of TMB-high or strong positive PD-L1 expression than the total EGFR mutation group. In addition, different subtypes have different characteristics related to the immune microenvironment, such as G719 mutations being associated with more CD8+ T cell infiltration into tumors; except for EGFR 19del, CD8+ T cell infiltration into tumors of other EGFR mutation subtypes were similar to that of wildtype EGFR. Moreover, follow-up results revealed that components of the immune microenvironment have prognostic value for NSCLC patients, with different prognostic biomarkers for NSCLC patients with and without EGFR mutations. These results suggest that patients with different EGFR mutations need to be treated differently. The prognosis of NSCLC patients may be assessed through components of tumor immune microenvironment, and ICIs treatment may be considered for those with some uncommon EGFR mutation subtypes.

Identification of a novel autophagy signature for predicting survival in patients with lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most commonhistological lung cancer subtype, with an overall five-year survivalrate of only 17%. In this study, we aimed to identify autophagy-related genes (ARGs) and develop an LUAD prognostic signature. METHODS: In this study, we obtained ARGs from three databases and downloaded gene expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We used TCGA-LUAD (n = 490) for a training and testing dataset, and GSE50081 (n = 127) as the external validation dataset.The least absolute shrinkage and selection operator (LASSO) Cox and multivariate Cox regression models were used to generate an autophagy-related signature. We performed gene set enrichment analysis (GSEA) and immune cell analysis between the high- and low-risk groups. A nomogram was built to guide the individual treatment for LUAD patients. RESULTS: We identified a total of 83 differentially expressed ARGs (DEARGs) from the TCGA-LUAD dataset, including 33 upregulated DEARGs and 50 downregulated DEARGs, both with thresholds of adjusted P < 0.05 and |Fold change| > 1.5. Using LASSO and multivariate Cox regression analyses, we identified 10 ARGs that we used to build a prognostic signature with areas under the curve (AUCs) of 0.705, 0.715, and 0.778 at 1, 3, and 5 years, respectively. Using the risk score formula, the LUAD patients were divided into low- or high-risk groups. Our GSEA results suggested that the low-risk group were enriched in metabolism and immune-related pathways, while the high-risk group was involved in tumorigenesis and tumor progression pathways. Immune cell analysis revealed that, when compared to the high-risk group, the low-risk group had a lower cell fraction of M0- and M1- macrophages, and higher CD4 and PD-L1 expression levels. CONCLUSION: Our identified robust signature may provide novel insight into underlying autophagy mechanisms as well as therapeutic strategies for LUAD treatment.

Next-Generation Sequencing Reveals High Uncommon EGFR Mutations and Tumour Mutation Burden in a Subgroup of Lung Cancer Patients.

Xuanwei County in Southwest China shows the highest incidence and mortality rate of lung cancer in China. Although studies have reported distinct clinical characteristics of patients from Xuanwei, the molecular features of these patients with non-small cell lung cancer (NSCLC) remain unclear. Here, we comprehensively characterised such cases using next-generation sequencing (NGS). Formalin-fixed, paraffin-embedded tumour samples from 146 patients from Xuanwei with NSCLC were collected for an NGS-based target panel assay; their features were compared with those of reference Chinese and The Cancer Genome Atlas (TCGA) cohorts. Uncommon EGFR mutations, defined as mutations other than L858R, exon 19del, exon 20ins, and T790M, were the predominant type of EGFR mutations in the Xuanwei cohort. Patients harbouring uncommon EGFR mutations were more likely to have a family history of cancer (p = 0.048). A higher frequency of KRAS mutations and lower frequency of rearrangement alterations were observed in the Xuanwei cohort (p < 0.001). Patients from Xuanwei showed a significantly higher tumour mutation burden than the reference Chinese and TCGA cohorts (p < 0.001). Our data indicates that patients from Xuanwei with NSCLC harbouring G719X/S768I co-mutations may benefit from treatment with EGFR-tyrosine kinase inhibitors. Our comprehensive molecular profiling revealed unique genomic features of patients from Xuanwei with NSCLC, highlighting the potential for improvement in targeted therapy and immunotherapy.

DNA Repair-Based Gene Expression Signature and Distinct Molecular Subtypes for Prediction of Clinical Outcomes in Lung Adenocarcinoma.

Objective: To conduct a robust prognostic gene expression signature and characterize molecular subtypes with distinct clinical characteristics for lung adenocarcinoma (LUAD). Methods: Based on DNA repair genes from the GSEA database, a prognostic signature was conducted in the TCGA-LUAD training set via univariate and multivariate cox regression analysis. Its prediction power was validated by overall survival analysis, relative operating characteristic (ROC) curves and stratification analysis in the GSE72094 verification set. Involved pathways in the high- and low-risk groups were analyzed by GSEA. A nomogram was built based on the signature and clinical features and its performance was assessed by calibration plots. LUAD samples were clustered via the ConsensusClusterPlus package. The differences in clinical outcomes, single nucleotide polymorphism (SNP) and sensitivity to chemotherapy drugs between molecular subtypes were analyzed. Results: A 13-DNA repair gene-signature was constructed for LUAD prognosis. Following validation, it can robustly and independently predict patients' clinical outcomes. The GSEA results exhibited the differences in pathways between high- and low- risk groups. A nomogram combining the signature and stage could accurately predict 1-, 3-, and 5-year survival probability. Two distinct molecular subtypes were characterized based on DNA repair genes. Patients in the Cluster 2 exhibited a worse prognosis and were more sensitive to common chemotherapy than those in the Cluster 1. Conclusion:This study proposed a 13-DNA repair gene-signature as a prognostic factor for LUAD patients, which can independently predict clinical outcomes by complement of the stage. Moreover, we characterized two LUAD subtypes with distinct clinical outcomes, somatic gene mutations, and drug sensitivity in cancer based on DNA repair genes.

Identification of alternative splicing and lncRNA genes in pathogenesis of small cell lung cancer based on their RNA sequencing.

BACKGROUND: The molecular mechanisms involved in small-cell lung cancer (SCLC) are largely unknown. Recent studies have suggested that long non-coding RNAs (lncRNAs) are likely to play a critical role. OBJECTIVES: There is an urgent need for suitable molecular biomarkers for SCLC diagnosis and for assessing patient prognosis. MATERIAL AND METHODS: In this study, we used public databases to identify mRNA-like candidate lncRNAs. A multi-step computational approach was used to construct a functional SCLC lncRNAs-mediated competing with endogenous RNA (ceRNA) network (LMCN) by integrating genome-wide lncRNAs and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. RESULTS: The results revealed the significance of lncRNAs interactions with ceRNAs in SCLC, indicating that integration of expression profiles and alternative splicing could be used to identify biomarkers and the underlying pathological changes. The following genes: EPB41L4A-AS1, HOXA-AS2, XIST, DLEU2, FGD5-AS1, ALMS1-IT1, SNHG12, MIR17HG, MIR4720, and SCARNA10 in cluster, as well as shared alternative splicing events, were considered to be critical genes. CONCLUSIONS: Olfactory transduction and endocytosis were the top-enriched pathways in SCLC. The selected cluster, including critical genes, might also be a potential pathway of SCLC pathogenesis. As a result, this research provides the perspective information to explore the potential critical genes and its pathways in SCLC therapy.

Primary hepatoid adenocarcinoma of the lung in Yungui Plateau, China: A case report.

BACKGROUND: Hepatoid adenocarcinoma (HAC) occurs in extrahepatic organs such as the gastrointestinal tract, testes, ovaries, lungs, mediastinum and pancreas, and frequently produces α-fetoprotein (AFP). HAC of the lung (HAL) is rare, characterized by difficult treatment and poor prognosis. There are no reports of HAL in Yunnan-Guizhou Plateau, China. CASE SUMMARY: A 60-year-old male patient was clinically diagnosed with HAL pT3N0M0, stage IIB. Chest computed tomography revealed a 7.5 cm × 7.2 cm soft tissue mass located in the right lung upper lobe and the adjacent superior mediastinum. Right upper lobectomy was performed. The diagnosis of HAL was confirmed by pathological examination, and the patient received paclitaxel and carboplatin as adjuvant chemotherapy after surgery. CONCLUSION: Clinical manifestations, pathological features, imaging findings, auxiliary examination, and treatment planning of HAL are presented to help clinicians improve their diagnosis and treatment.