A functional network of gastric-cancer-associated splicing events controlled by dysregulated splicing factors

Abstract Comprehensive understanding of aberrant splicing in gastric cancer is lacking. We RNA-sequenced 19 gastric tumor–normal pairs and identified 118 high-confidence tumor-associated (TA) alternative splicing events (ASEs) based on high-coverage sequencing and stringent filtering, and also identified 8 differentially expressed splicing factors (SFs). The TA ASEs occurred in genes primarily involved in cytoskeletal organization. We constructed a correlative network between TA ASE splicing ratios and SF expression, replicated it in independent gastric cancer data from The Cancer Genome Atlas and experimentally validated it by knockdown of the nodal SFs (PTBP1, ESRP2 and MBNL1). Each SF knockdown drove splicing alterations in several corresponding TA ASEs and led to alterations in cellular migration consistent with the role of TA ASEs in cytoskeletal organization. We have therefore established a robust network of dysregulated splicing associated with tumor invasion in gastric cancer. Our work is a resource for identifying oncogenic splice forms, SFs and splicing-generated tumor antigens as biomarkers and therapeutic targets.

Download Full-text

Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

10.21203/rs.3.rs-183022/v1 ◽

2021 ◽

Author(s):

Zhiwu Wang ◽

Qiong Wu ◽

Yankun Liu ◽

Jingwu Li

Keyword(s):

Gastric Cancer ◽

Alternative Splicing ◽

Clinical Information ◽

The Cancer Genome Atlas ◽

Prognostic Indicators ◽

Splicing Factors ◽

Rna Seq ◽

Oncogenic Pathways ◽

Splicing Variants ◽

Cancer Genome Atlas

Abstract Aberrant alternative splicing (AS) events serve as prognostic indicators in a large number of malignancies, whereas comprehensive analysis of prognostic AS in gastric cancer (GC) has not yet been understood. To identify prognostic AS events and clarify the function of the splicing variants in GC. RNA-Seq data, clinical information and percent spliced in (PSI) values were available in the cancer genome atlas (TCGA) and TCGA SpliceSeq data portal. A three-step regression method was conducted to screen prognostic AS events and construct multi-AS-based signatures. The associations between prognostic AS events and splicing factors were also investigated. We identified a total of 1318 survival related AS events in GC, Parent genes of which were implicated in numerous oncogenic pathways. The final prognostic signatures stratified by seven types of AS events or not stratified performed well in risk prediction for GC patients. Moreover, five signatures base on AA, AD, AT, ES and RI events function as independent prognostic indicators after multivariate adjustment of clinicalpathological variables. Splicing network also showed marked correlation between the expression of splicing factors and PSI value of AS events in GC patients. The AS derived signatures allow to predict GC prognosis and might serve as potential therapeutic target for GC.

Download Full-text

The Prognostic Significance of MAFK and its Methylation in Cervical Cancer

10.21203/rs.3.rs-582069/v1 ◽

2021 ◽

Author(s):

Mengjun Zhang ◽

Hao Li ◽

Yuan Liu ◽

Siyu Hou ◽

Ping Cui ◽

...

Keyword(s):

Cervical Cancer ◽

Prognostic Significance ◽

Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cancer Prognosis ◽

Aberrant Methylation ◽

Cancer Data ◽

Drug Candidates ◽

Cancer Genome Atlas ◽

Cancer Tissues

Abstract Background: The purpose of this study was to determine the value of MAFK as a biomarker of cervical cancer prognosis and to explore its methylation and possible cellular signaling pathways. Methods: We analyzed the cervical cancer data of The Cancer Genome Atlas (TCGA) through bioinformatics, including MAFK expression, methylation, prognosis and genome enrichment analysis. Results: MAFK expression was higher in cervical cancer tissues and was negatively correlated with the methylation levels of five CpG sites. MAFK is an independent prognostic factor of cervical cancer and is involved in the Nod-like receptor signaling pathway. CMap analysis screened four drug candidates for cervical cancer treatment. Conclusions: We confirmed that MAFK is a novel prognostic biomarker for cervical cancer and aberrant methylation may also affect MAFK expression and carcinogenesis. This study provides a new molecular target for the prognostic evaluation and treatment of cervical cancer.

Download Full-text

Krüppel-Like Factor 7 is a Marker of Aggressive Gastric Cancer and Poor Prognosis

Cellular Physiology and Biochemistry ◽

10.1159/000481748 ◽

2017 ◽

Vol 43 (3) ◽

pp. 1090-1099 ◽

Cited By ~ 11

Author(s):

Zhonghua Jiang ◽

Tingting Yu ◽

Zhining Fan ◽

Hongmei Yang ◽

Xin Lin

Keyword(s):

Gastric Cancer ◽

Disease Free Survival ◽

Clinicopathological Characteristics ◽

The Cancer Genome Atlas ◽

Strong Negative Correlation ◽

Functional Studies ◽

Expression Of Genes ◽

Cancer Genome Atlas

Background/Aims: Krüppel-like factor (KLF) 7 protein is a member of the KLF transcription factor family, which plays important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation and metabolism. However, the role of KLF7 in gastric cancer (GC) is unknown. The aim of this study is to explore the role of KLF7 in GC and its correlation with clinicopathological characteristics and prognosis of GC patients. Methods: We first systematically evaluated dysregulation of the KLF family in The Cancer Genome Atlas (TCGA) GC database. Then, 252 patients who underwent surgery for GC were enrolled to validate the results from the TCGA. Functional studies were also used to explore the role of KLF7 in GC. Results: In the TCGA database, we found that KLF7 was an independent predictor for survival by both univariate and multivariate analysis (P<0.05). In a validation cohort, KLF7 expression was significantly increased in GC tissues compared with adjacent normal controls (P=0.013). High KLF7 expression correlated with inferior prognostic factors, such as T stage (P=0.022), N stage (P =0.005) and lymphovascular invasion (P=0.009). Furthermore, we observed a strong negative correlation between KLF7 expression and 5-year overall survival and disease-free survival in GC patients (P<0.05). Moreover, our in vitro studies showed a notable decrease in migration in KLF7 knockdown cells. Conclusion: KLF7 has an important role in GC progression, as it inhibits GC cell migration and may serve as a prognostic marker.

Download Full-text

CPXM1: a novel biomarker for gastric cancer prognosis

10.21203/rs.3.rs-337128/v1 ◽

2021 ◽

Author(s):

Jun Du ◽

Mengxiang Zhu ◽

Wenwu Yan ◽

Changsheng Yao ◽

Qingyi Li ◽

...

Keyword(s):

Gastric Cancer ◽

Poor Prognosis ◽

The Cancer Genome Atlas ◽

Cancer Prognosis ◽

Signal Pathways ◽

Data Set ◽

Kaplan Meier ◽

Cancer Genome Atlas ◽

Cox Proportional Hazard Regression ◽

The Relationship

Abstract Background The molecular role of carboxypeptidase X, M14 family member (CPXM1) in oncogenesis or tumor progression remains unclear. The aim of this study was to determine whether CPXM1 can be used as a potential prognostic biomarker for gastric cancer (GC). Methods We first demonstrated the relationship between CPXM1 expression and GC in various public databases. Secondly, the expression of CPXM1 in GC tissues was further verified by immunohistochemical staining using tissue microarray containing 96 cases of GC patients. Kaplan–Meier analysis and a Cox proportional hazard regression model were performed to evaluate the relationship between the expression of CPXM1 and the survival of GC patients. Finally, we used the expression data of CPXM1 in The Cancer Genome Atlas database to predict CPXM1-related signaling pathways through bioinformatics analysis. Results The expression level of CPXM1 in GC tissues was significantly correlated with tumor size (p = 0.041) and lymph node metastasis (p = 0.014). In addition, Kaplan–Meier analysis showed that the expression of CPXM1 in GC tissues was significantly associated with poor prognosis (p = 0.011). Multivariate analysis indicated that CPXM1 is a potential predictor of poor prognosis in GC patients (p = 0.026). The results of biosynthesis analysis demonstrated that the data set of CPXM1 high expression was mainly enriched in cancer-related signal pathways. Conclusion CPXM1 is an effective biomarker for the prognosis of GC patients and may play a key role in the occurrence and progression of GC.

Download Full-text

The Biological Function Delineated Across Pan-Cancer Levels Through lncRNA-Based Prognostic Risk Assessment Factors for Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.694652 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xudong Tang ◽

Mengyan Zhang ◽

Liang Sun ◽

Fengyan Xu ◽

Xin Peng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Prognostic Marker ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Research Network ◽

Molecular Characteristics ◽

Cancer Data ◽

Cancer Genome Atlas ◽

Pan Cancer ◽

Genome Atlas

Long non-coding RNAs (lncRNAs) play key roles in tumors and function not only as important molecular markers for cancer prognosis, but also as molecular characteristics at the pan-cancer level. Because of the poor prognosis of pancreatic cancer, accurate assessment of prognosis is a key issue in the development of treatment plans for pancreatic cancer. Here we analyzed pancreatic cancer data from The Cancer Genome Atlas and The Genotype Tissue Expression database using Cox regression and lasso regression in analyses using a combination of the two databases as well as only The Cancer Genome Atlas database (Cancer Genome Atlas Research Network et al., 2013). A prognostic risk score model with significant correlation with pancreatic cancer survival was constructed, and two lncRNAs were investigated. Additional analysis of 33 cancers using the two lncRNAs showed that lncRNA TsPOAP1-AS1 was a prognostic marker of seven cancers, among which pancreatic cancer was the most significant, and lncRNA mi600hg was a prognostic marker of ovarian cancer and pancreatic cancer. LncRNA TsPOAP1-AS1 is associated with clinical stage and tumor mutation burden of some cancers as well as a strong degree of immune infiltration in many cancers, while a strong correlation between lncRNA mi600hg and microsatellite instability was observed in several cancers. The results of this study help further our understanding of the different functions of lncRNAs in cancer and may aid in the clinical application of lncRNAs as prognostic factors for cancer.

Download Full-text

Why MUC16 mutations lead to a better prognosis: A study based on The Cancer Genome Atlas gastric cancer cohort

World Journal of Clinical Cases ◽

10.12998/wjcc.v9.i17.4143 ◽

2021 ◽

Vol 9 (17) ◽

pp. 4143-4158

Author(s):

Yu-Jie Huang ◽

Zhi-Fei Cao ◽

Jie Wang ◽

Jian Yang ◽

Yi-Jun Wei ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Cancer Genome Atlas ◽

Genome Atlas

Download Full-text

Candidate genes for predicting the survival of patients with gastric cancer: a study based on The Cancer Genome Atlas (TCGA) database

Translational Cancer Research ◽

10.21037/tcr.2020.02.82 ◽

2020 ◽

Vol 9 (4) ◽

pp. 2599-2608

Author(s):

Xiqiao Liu ◽

Liying Gao ◽

Dongqiong Ni ◽

Chengao Ma ◽

Yuping Lu ◽

...

Keyword(s):

Gastric Cancer ◽

Candidate Genes ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Cancer Genome Atlas ◽

Genome Atlas

Download Full-text

Tumor microenvironment characterization in stage IV gastric cancer

Bioscience Reports ◽

10.1042/bsr20201248 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Xianxue Zhang ◽

Feng Yang ◽

Zhenbao Wang

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Stage Iv ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Stage Iv Gastric Cancer ◽

Th 17 ◽

Cancer Genome Atlas

Abstract Immunotherapy is remarkably affected by the immune environment of the principal tumor. Nonetheless, the immune environment’s clinical relevance in stage IV gastric cancer (GC) is largely unknown. The gene expression profiles of 403 stage IV GC patients in the three cohorts: GEO (Gene Expression Omnibus, GSE84437 (n=292) and GSE62254 (n=77), and TCGA (The Cancer Genome Atlas, n=34) were used in the present study. Using four publicly available stage IV GC expression datasets, 29 immune signatures were expression profiled, and on this basis, we classified stage IV GC. The classification was conducted using the hierarchical clustering method. Three stage IV GC subtypes L, M, and H were identified representing low, medium, and high immunity, respectively. Immune correlation analysis of these three types revealed that Immune H exhibited a better prognostic outcome as well as a higher immune score compared with other subtypes. There was a noticeable difference in the three subgroups of HLA genes. Further, on comparing with other subtypes, CD86, CD80, CD274, CTLA4, PDCD1, and PDCD1LG2 had higher expression in the Immunity H subtype. In stage IV GC, potentially positive associations between immune and pathway activities were displayed, due to the enrichment of pathways including TNF signaling, Th-17 cell differentiation, and JAK-STAT signaling pathways in Immunity H vs Immunity L subtypes. External cohorts from TCGA cohort ratified these results. The identification of stage IV GC subtypes has potential clinical implications in stage IV GC treatment.

Download Full-text

Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients

Disease Markers ◽

10.1155/2021/9980410 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jean Paul Nshizirungu ◽

Sanae Bennis ◽

Ihsane Mellouki ◽

Mohammed Sekal ◽

Dafr-Allah Benajah ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Research ◽

Overall Survival ◽

Molecular Subtypes ◽

Clinicopathological Features ◽

The Cancer Genome Atlas ◽

Cancer Genome Atlas ◽

Gastric Cancer Patients ◽

Genome Atlas ◽

E Cadherin

Introduction. The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis. Methods. Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI). Results. Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). Discussion/Conclusion. We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.

Download Full-text