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.

Non-SMC Condensin I Complex Subunit D2 Is a Prognostic Factor in Triple-Negative Breast Cancer for the Ability to Promote Cell Cycle and Enhance Invasion.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with an unfavorable prognosis and no specific targeted therapies. The role of non-SMC condensin I complex subunit D2 (NCAPD2), a regulatory subunit of the condensin I complex that mainly participates in chromosome condensation and segregation, has not been reported in cancer. We therefore evaluated the prognostic value and biological function of NCAPD2 in TNBC. The expression of NCAPD2 was studied in 179 TNBC tissues by immunohistochemistry, and associations among NCAPD2 expression, clinicopathologic features, and the prognosis information of patients with TNBC were analyzed. The mRNA expression profiles of 99 TNBC tissues were also studied, and cell biological behaviors were detected when NCAPD2 was altered in three TNBC cell lines. NCAPD2 expression was positively associated with lymph node metastasis (P = 3.84 × 10-06), poor overall survival (P = 0.0033), and worse disease-free survival (P = 0.0013) of patients with TNBC. Moreover, knockdown of NCAPD2 might cause G2/M arrest through the p53 signaling pathway, which led to proliferation inhibition, polyploid cell production, and cell apoptosis and inhibited the invasiveness of TNBC cells. For the first time, we report the close association between NCAPD2 and cancer and demonstrate that NCAPD2 plays an important role in TNBC progression and acts as an independent poor prognostic factor and a potential therapeutic target for TNBC.

A novel signature for stratifying the molecular heterogeneity of the tissue-infiltrating T-cell receptor repertoire reflects gastric cancer prognosis.

Many basic properties of the T-cell receptor (TCR) repertoire require clarification, and the changes occurring in the TCR repertoire during carcinogenesis, especially during precancerous stages, remain unclear. This study used deep sequencing analyses to examine 41 gastric tissue samples at different pathological stages, including low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, early gastric cancer and matched adjacent tissues, to define the characteristics of the infiltrating TCRß repertoire during gastric carcinogenesis. Moreover, to illustrate the relationship between the local molecular phenotype and TCR repertoire of the microenvironment, whole-genome gene expression microarray analysis of the corresponding gastric precancerous lesions and early gastric cancer tissues was conducted. Our results showed that the degree of variation in the TCR repertoire gradually increased during tumourigenesis. Integrative analysis of microarray data and the TCR repertoire variation index using the network-based Clique Percolation Method identified an 11-gene module related to the inflammatory response that can predict the overall survival of gastric cancer (GC) patients. In conclusion, our results revealed the multistage heterogeneity of tissue-infiltrating TCR repertoire during carcinogenesis. We report a novel way for identifying prognostic biomarkers for GC patients and improves our understanding of immune responses during gastric carcinogenesis.

Heterogeneity of tumor-infiltrating lymphocytes ascribed to local immune status rather than neoantigens by multi-omics analysis of glioblastoma multiforme.

Hypothetically, intratumoral genomic heterogeneity has the potential to foster tumor-infiltrating lymphocyte (TIL) diversity; however, no study has directly tested this hypothesis by simultaneously investigating somatic mutations, TIL diversity, and immune response activity. Thus, we performed whole-exome sequencing, immune repertoire sequencing and gene expression on ten spatially separated tumor samples obtained from two tumor masses excised from a glioblastoma multiforme (GBM) patient, and we included peripheral blood as control. We found that although the multi-region samples from one tumor shared more common mutations than those from different tumors, the TIL populations did not. TIL repertoire diversity did not significantly correlate with the number of non-synonymous mutations; however, TIL diversity was highly correlated with local immune activity, as the pathways were all immune-related pathways that highly positive correlated with local TIL diversity. Twenty-three genes with expression largely unaffected by the intratumor heterogeneity were extracted from these pathways. Fifty GBM patients were stratified into two clusters by the expression of these genes with significant difference in prognosis. This finding was validated by The Cancer Genome Atlas (TCGA) GBM dataset, which indicated that despite the heterogeneity of intra-tumor immune status, the overall level of the immune response in GBM could be connected with prognosis.

SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression.

Structural maintenance of chromosome 4 (SMC4) is a core subunit of condensin complexes that mainly contributes to chromosome condensation and segregation. Our previous study demonstrated that the gene expression profile during lung development is of great values for the study of lung cancer. In this study, we identified SMC4 through co-expression network analysis and clique percolation clustering using genes that constant changes during four stages of lung development. Gene ontology and KEGG pathway enrichment analysis demonstrated that SMC4 is closely related to cell cycle, cell adhesion, and RNA processing in lung development and carcinogenesis. Moreover, SMC4 is overexpressed in lung adenocarcinoma tissues and acts as an independent prognostic factor. SMC4 knockdown significantly inhibits the proliferation and invasion of A549 cells. Furthermore, we found that SMC4 interacts with DDX46 (DEAD-box helicase 46). In conclusion, the pivotal role of SMC4 in lung development and carcinogenesis suggests that genes with a similar expression pattern to SMC4 in lung development may also contribute to lung cancer progression. The identification of genes that are essentially involved in development through a comparative study between development and cancer may be a practical strategy for discovering potential biomarkers and illuminating the mechanisms of carcinogenesis.

Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde?

Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment.