Peripheral blood transcriptome heterogeneity and prognostic potential in lung cancer revealed by RNA-Seq.

Understanding of the complex interaction between the peripheral immune system and lung cancer (LC) remains incomplete, limiting patient benefit. Here, we aimed to characterize the host peripheral immune response to LC and investigate its potential prognostic value. Bulk RNA-sequencing data of peripheral blood leucocytes (PBLs) from healthy volunteers and LC patients (n = 142) were analysed for characterization of host systemic immunity in LC. We observed broad blood transcriptome perturbations in LC patients that were heterogeneous, as two new subtypes were established independent of histology. Functionally, the heterogeneity between the two subtypes included dysregulation of diverse biological processes, such as the cell cycle, blood coagulation and inflammatory signalling pathways, together with the abundance and activity of blood cells, particularly lymphocytes and neutrophils, ultimately manifesting as differences in antitumour immune status. Based on these findings, a prognostic model composed of ten genes dysregulated in one LC subtype with relatively poor immune status was developed and validated in a Gene Expression Omnibus (GEO) data set (n = 108), helping to generate a prognostic nomogram. Collectively, our study provides novel and comprehensive insight into the heterogeneity of the host peripheral immune response to LC. The expression heterogeneity-based predictive model may help guide prognostic management for LC patients.

The landscape and biological relevance of aberrant alternative splicing events in esophageal squamous cell carcinoma.

Aberrant alternative splicing events (AASEs) are key biological processes for tumorigenesis and the rationale for designing splice-switching oligonucleotides (SSOs). However, the landscape of AASEs in esophageal squamous cell carcinoma (ESCC) remains unclear, which undermines the development of SSOs for ESCC. Here, we profiled AASEs based on 125 pairs of RNA-seq libraries. We identified 14,710 AASEs in ESCC, most of which (92.67%) affected coding genes. The first exon of transcripts was frequently changed in ESCC. We constructed a regulatory network where 74 RNA-binding proteins regulated 2142 AASEs. This network was enriched in apoptotic pathways and various adhesion/junction-related processes. Somatic mutations in ESCC regulating ASEs were mainly through trans-regulatory mode and were enriched in intron regions. Isoform switches of apoptotic genes and binding genes both tended to induce "noncoding transcripts" and "domain loss," disrupting the apoptotic and Hippo signaling pathways. All ESCC samples were grouped into three clusters with different AASEs patterns and the second cluster was identified as "cold tumor," with a low abundance of immune cells, activated immune pathways, and immunomodulators. Our work comprehensively profiled the landscape of AASEs in ESCC, revealed novel AASEs related to tumorigenesis and immune microenvironment, and suggested promising directions for designing SSOs for ESCC.

Molecular analysis of Chinese oesophageal squamous cell carcinoma identifies novel subtypes associated with distinct clinical outcomes.

BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is a highly heterogeneous cancer with a distinct incidence and prognosis. Molecular events driving ESCC subtypes and prognosis have not been established, and little is known regarding Chinese ESCC patients in Xinjiang, China. METHODS: Here, we first integrated the genomic and transcriptomic data of 125 Chinese ESCC patients from Xinjiang Tumor Hospital (Urumqi, China). Two independent datasets of GSE53624 and The Cancer Genome Atlas (TCGA) ESCC were used to confirm the results of this study. DNA mutation and overall survival (OS) were analysed independently in the Chinese ESCC cohorts. FINDINGS: Genomic analyses revealed a consistent mutation signatures and discordance among mutated genes across the different ESCC cohorts. In addition, transcriptomic profiling identified three Chinese ESCC subtypes associated with clinical and molecular attributes, including patient survival, lymph node status and genetic profile. Moreover, Chinese ESCC subtypes have distinct metabolic, inflammatory, metastatic, and cell proliferation features and unique potential therapeutics. Furthermore, the expression of cell cycle- and/or cell proliferation-related genes was higher in cyclin D1 (CCND1)-amplified tumours than in CCND1-normal tumours from Chinese ESCC patients, suggesting that CCND1 amplification promoted cell proliferation. INTERPRETATION: Our findings provide a framework to facilitate the rational categorization of ESCC in Chinese patients and a foundation for new therapies. FUNDING: This study was supported by the Research Fund of Key Laboratory of Xinjiang oncology (Grant no.2017D04006) and the Outstanding Youth Science and technology training project fund of Xinjiang, China (Grant no. 2017Q058).