Identification of Prognostic Alternative Splicing Signature in Gastric Cancer

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.

scholarly journals Characterization of alternative splicing events and prognostic signatures in breast cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Pihua Han ◽  
Jingjun Zhu ◽  
Guang Feng ◽  
Zizhang Wang ◽  
Yanni Ding
Keyword(s):  
Breast Cancer ◽  
Alternative Splicing ◽  
Proportional Hazards ◽  
Pearson Correlation ◽  
Original Data ◽  
Cox Proportional Hazards ◽  
Prognostic Indicators ◽  
Splicing Factors ◽  
Rna Seq

Abstract Background Breast cancer (BRCA) is one of the most common cancers worldwide. Abnormal alternative splicing (AS) frequently observed in cancers. This study aims to demonstrate AS events and signatures that might serve as prognostic indicators for BRCA. Methods Original data for all seven types of splice events were obtained from TCGA SpliceSeq database. RNA-seq and clinical data of BRCA cohorts were downloaded from TCGA database. Survival-associated AS events in BRCA were analyzed by univariate COX proportional hazards regression model. Prognostic signatures were constructed for prognosis prediction in patients with BRCA based on survival-associated AS events. Pearson correlation analysis was performed to measure the correlation between the expression of splicing factors (SFs) and the percent spliced in (PSI) values of AS events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted to demonstrate pathways in which survival-associated AS event is enriched. Results A total of 45,421 AS events in 21,232 genes were identified. Among them, 1121 AS events in 931 genes significantly correlated with survival for BRCA. The established AS prognostic signatures of seven types could accurately predict BRCA prognosis. The comprehensive AS signature could serve as independent prognostic factor for BRCA. A SF-AS regulatory network was therefore established based on the correlation between the expression levels of SFs and PSI values of AS events. Conclusions This study revealed survival-associated AS events and signatures that may help predict the survival outcomes of patients with BRCA. Additionally, the constructed SF-AS networks in BRCA can reveal the underlying regulatory mechanisms in BRCA.

scholarly journals IsoformSwitchAnalyzeR: analysis of changes in genome-wide patterns of alternative splicing and its functional consequences

2019 ◽  
Vol 35 (21) ◽  
pp. 4469-4471 ◽  
Author(s):  
Kristoffer Vitting-Seerup ◽  
Albin Sandelin
Keyword(s):  
Alternative Splicing ◽  
The Cancer Genome Atlas ◽  
Supplementary Information ◽  
Rna Seq ◽  
Genome Wide ◽  
Functional Consequences ◽  
Cancer Genome Atlas ◽  
Health And Disease ◽  
Splicing Patterns

Abstract Summary Alternative splicing is an important mechanism involved in health and disease. Recent work highlights the importance of investigating genome-wide changes in splicing patterns and the subsequent functional consequences. Current computational methods only support such analysis on a gene-by-gene basis. Therefore, we extended IsoformSwitchAnalyzeR R library to enable analysis of genome-wide changes in specific types of alternative splicing and predicted functional consequences of the resulting isoform switches. As a case study, we analyzed RNA-seq data from The Cancer Genome Atlas and found systematic changes in alternative splicing and the consequences of the associated isoform switches. Availability and implementation Windows, Linux and Mac OS: http://bioconductor.org/packages/IsoformSwitchAnalyzeR. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Potential prognostic impact of EBV RNA‐seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort

FEBS Open Bio ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 455-467 ◽  
Author(s):  
Daichi Sadato ◽  
Mina Ogawa ◽  
Chizuko Hirama ◽  
Tsunekazu Hishima ◽  
Shin‐Ichiro Horiguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Prognostic Impact ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

scholarly journals hnRNPA2B1 regulates the alternative splicing of BIRC5 to promote gastric cancer progression

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei-zhao Peng ◽  
Jin Zhao ◽  
Xin Liu ◽  
Chao-feng Li ◽  
Shuang Si ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Cell Metastasis ◽  
Rna Immunoprecipitation ◽  
Cancer Genome Atlas ◽  
Underlying Mechanisms ◽  
Important Disease

Abstract Background Systematic profiling studies have implicated regulators of pre-mRNA splicing as important disease determinants in gastric cancer (GC), but the underlying mechanisms have remained elusive. Here we focused on hnRNPA2B1 splicing factor-dependent mechanisms governing GC development. Methods The expression of hnRNPA2B1 was analyzed among the Cancer Genome Atlas (TCGA) datasets of GC and validated at mRNA level. The function of hnRNPA2B1 in GC cells was analyzed and its downstream gene was identified using RNA immunoprecipitation. Further, effect of hnRNPA2B1 on BIRC5 alternative splicing was investigated. Results We show that overexpression of hnRNPA2B1 in GC is correlated with poor survival, and hnRNPA2B1 is required for maintaining GC malignant phenotype by promoting cell proliferation, inhibiting cell apoptosis and increasing cell metastasis. Mechanistically, hnRNPA2B1 co-expressed with several core spliceosome components and controls alternative splicing of anti-apoptotic factor BIRC5. BIRC5 isoform 202 (BIRC5-202) played the oncogenic function in GC cells, and overexpression of the BIRC5-202 transcript partly rescued the decrease in cisplatin resistance induced by downregulation of hnRNPA2B1. Conclusions We demonstrate that hnRNPA2B1 regulates BIRC5 splicing and might act as a therapeutic target of chemo-resistant GC cells.

scholarly journals An interactive network of alternative splicing events with prognostic value in geriatric lung adenocarcinoma via the regulation of splicing factors

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Yidi Wang ◽  
Yaxuan Wang ◽  
Kenan Li ◽  
Yabing Du ◽  
Kang Cui ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Lung Adenocarcinoma ◽  
Prognostic Value ◽  
Prognostic Index ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Splicing Factors ◽  
Systematic Analysis ◽  
Interactive Network ◽  
Underlying Mechanisms

Abstract Alternative splicing (AS), an essential process for the maturation of mRNAs, is involved in tumorigenesis and tumor progression, including angiogenesis, apoptosis, and metastasis. AS changes can be frequently observed in different tumors, especially in geriatric lung adenocarcinoma (GLAD). Previous studies have reported an association between AS events and tumorigenesis but have lacked a systematic analysis of its underlying mechanisms. In the present study, we obtained splicing event information from SpliceSeq and clinical information regarding GLAD from The Cancer Genome Atlas. Survival-associated AS events were selected to construct eight prognostic index (PI) models. We also constructed a correlation network between splicing factors (SFs) and survival-related AS events to identify a potential molecular mechanism involved in regulating AS-related events in GLAD. Our study findings confirm that AS has a strong prognostic value for GLAD and sheds light on the clinical significance of targeting SFs in the treatment of GLAD.

scholarly journals Identification of potential biomarkers and their clinical significance in gastric cancer using bioinformatics analysis methods

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9174
Author(s):  
Jie Liu ◽  
Miao Zhou ◽  
Yangyang Ouyang ◽  
Laifeng Du ◽  
Lingbo Xu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alternative Splicing ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
Clinical Information ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Independent Prognostic Marker ◽  
Normal Tissues ◽  
Gastric Cancer Patients

Background Alternative splicing (AS) is an important mechanism for regulating gene expression and proteome diversity. Tumor-alternative splicing can reveal a large class of new splicing-associated potential new antigens that may affect the immune response and can be used for immunotherapy. Methods The RNA-seq transcriptome data and clinical information of stomach adenocarcinoma (STAD) cohort were downloaded from The Cancer Genome Atlas (TCGA) database data portal, and data of splicing events were obtained from the SpliceSeq database. Predicting genes were validated by Asian cancer research group (ACRG) cohort and Oncomine database. RT-qPCR was used to analysis the expression of ECT2 in STAD. Results A total of 32,166 AS events were identified, among which 2,042 AS events were significantly associated with patients survival. Biological pathway analysis indicated that these genes play an important role in regulating gastric cancer-related processes such as GTPase activity and PI3K-Akt signaling pathway. Next, we derived a risk signature, using alternate acceptor, that is an independent prognostic marker. Moreover, high ECT2 expression was associated with poorer prognosis in STAD. Multivariate survival analysis demonstrated that high ECT2 expression was an independent risk factor for overall survival. Gene set enrichment analysis revealed that high ECT2 expression was enriched for hallmarks of malignant tumors. The ACRG cohort and Oncomine also showed that high ECT2 expression was associated with poorer prognosis in gastric cancer patients. Finally, RT-qPCR showed ECT2 expression was higher in STAD compared to the normal tissues. Conclusion This study excavated the alternative splicing events in gastric cancer, and found ECT2 might be a biomarkers for diagnosis and prognosis.

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

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Shanshan Cheng ◽  
Debleena Ray ◽  
Raymond Teck Ho Lee ◽  
Kishore Babu Naripogu ◽  
Permeen Akhtar Bt Mohamed Yusoff ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Antigens ◽  
Cellular Migration ◽  
The Cancer Genome Atlas ◽  
Splicing Factors ◽  
High Coverage ◽  
Cytoskeletal Organization ◽  
Cancer Data ◽  
Cancer Genome Atlas ◽  
Splice Forms

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.

UBE3C promotes proliferation and inhibits apoptosis by activating the β-catenin signaling via degradation of AXIN1 in gastric cancer

2020 ◽  
Author(s):  
Yu Zhang ◽  
Jiapeng Xu ◽  
Hongbing Fu ◽  
Ziran Wei ◽  
Dejun Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Ubiquitin Ligase ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Potential Therapeutic Target ◽  
Nude Mouse Model ◽  
Tumor Tissues ◽  
Cancer Genome Atlas

Abstract Gastric cancer (GC) remains one of the most frequent cancers worldwide. Previous studies have shown that E3 ubiquitin ligase E3C (UBE3C) promotes the progression of multiple types of cancer. However, little is known about the expression and molecular mechanism of UBE3C in GC. In this study, UBE3C is upregulated in clinical GC samples and RNA-seq data from The Cancer Genome Atlas, and the UBE3C upregulation is correlated with poor clinical outcomes in patients with GC. In vitro, knockdown of UBE3C suppresses proliferation and enhances apoptosis in GC cells by inhibiting β-catenin signaling pathway. In contrast, in vitro overexpression of UBE3C promotes GC cell proliferation and inhibits apoptosis through the upregulation of β-catenin signaling by promoting ubiquitination of AXIN1. In vivo, knockdown of UBE3C inhibits tumor growth in a nude mouse model. Concurrently, the UBE3C knockdown resulted in an increase of AXIN1 and a reduction of β-catenin in the nucleus and cytoplasm in the xenograft tumor tissues. Our results demonstrate that UBE3C promotes GC progression through activating the β-catenin signaling via degradation of AXIN1. Our data suggest that UBE3C exerts oncogenic effects in GC and thus provides a promising prognostic biomarker and a potential therapeutic target for GC therapy.

scholarly journals IsoformSwitchAnalyzeR: Analysis of changes in genome-wide patterns of alternative splicing and its functional consequences

2018 ◽  
Author(s):  
Kristoffer Vitting-Seerup ◽  
Albin Sandelin
Keyword(s):  
Alternative Splicing ◽  
Recent Work ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Genome Wide ◽  
Functional Consequences ◽  
Cancer Genome Atlas ◽  
Health And Disease ◽  
Genome Atlas

AbstractAlternative splicing is an important mechanism involved in both health and disease. Recent work highlights the importance of investigating genome-wide changes in patters of splicing and the subsequent functional consequences. Unfortunately current computational methods only support such analysis on a gene-by-gene basis. To fill this gap, we extended IsoformSwitchAnalyzeR thereby enabling analysis of genome-wide changes in both specific types of alternative splicing as well as the predicted functional consequences of the resulting isoform switches. As a case study, we analyzed RNA-seq data from The Cancer Genome Atlas and found systematic changes in both alternative splicing and the consequences of the associated isoform switches.AvailabilityWindows, Linux and Mac OS: http://bioconductor.org/packages/IsoformSwitchAnalyzeR.ContactKVS: [email protected], AS: [email protected]

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