scholarly journals Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ana R Grosso ◽  
Ana P Leite ◽  
Sílvia Carvalho ◽  
Mafalda R Matos ◽  
Filipa B Martins ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Transcriptional Profiling ◽  
The Cancer Genome Atlas ◽  
Cancer Genes ◽  
Cell Renal Cell Carcinoma ◽  
Aberrant Expression ◽  
Chimeric Transcripts ◽  
Cancer Genome Atlas ◽  
Pervasive Transcription ◽  
Transcriptome Diversity

Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read-through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer.

scholarly journals A Novel m6A Gene Signature Associated With Regulatory Immune Function for Prognosis Prediction in Clear-Cell Renal Cell Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Siteng Chen ◽  
Ning Zhang ◽  
Encheng Zhang ◽  
Tao Wang ◽  
Liren Jiang ◽  
...  
Keyword(s):  
Risk Score ◽  
Clear Cell ◽  
Area Under The Curve ◽  
The Cancer Genome Atlas ◽  
Survival Prediction ◽  
Cell Renal Cell Carcinoma ◽  
Training Cohort ◽  
Rna Methylation ◽  
Cancer Genome Atlas ◽  
Genome Atlas

The important role of N6-methyladenosine (m6A) RNA methylation regulator in carcinogenesis and progression of clear-cell renal cell carcinoma (ccRCC) is poorly understood by now. In this study, we performed comprehensive analyses of m6A RNA methylation regulators in 975 ccRCC samples and 332 adjacent normal tissues and identified ccRCC-related m6A regulators. Moreover, the m6A diagnostic score based on ccRCC-related m6A regulators could accurately distinguish ccRCC from normal tissue in the Meta-cohort, which was further validated in the independent GSE-cohort and The Cancer Genome Atlas-cohort, with an area under the curve of 0.924, 0.867, and 0.795, respectively. Effective survival prediction of ccRCC by m6A risk score was also identified in the Cancer Genome Atlas training cohort and verified in the testing cohort and the independent GSE22541 cohort, with hazard ratio values of 3.474, 1.679, and 2.101 in the survival prognosis, respectively. The m6A risk score was identified as a risk factor of overall survival in ccRCC patients by the univariate Cox regression analysis, which was further verified in both the training cohort and the independent validation cohort. The integrated nomogram combining m6A risk score and predictable clinicopathologic factors could accurately predict the survival status of the ccRCC patients, with an area under the curve values of 85.2, 82.4, and 78.3% for the overall survival prediction in 1-, 3- and 5-year, respectively. Weighted gene co-expression network analysis with functional enrichment analysis indicated that m6A RNA methylation might affect clinical prognosis through regulating immune functions in patients with ccRCC.

scholarly journals LRG1 May Accelerate the Progression of ccRCC via the TGF-β Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Quan Hong ◽  
Shuqiang Wang ◽  
Shuxin Liu ◽  
Xiangmei Chen ◽  
Guangyan Cai
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kidney Tissue ◽  
The Cancer Genome Atlas ◽  
Gene Methylation ◽  
Cell Renal Cell Carcinoma ◽  
Tissue Samples ◽  
Downstream Signaling ◽  
Cancer Genome Atlas

Clear cell renal cell carcinoma (ccRCC) accounts for 60-70% of renal cell carcinoma (RCC) cases. It is an urgent mission to find more therapeutic targets for advanced ccRCC. Leucine-rich a-2-glycoprotein 1 (LRG1) is a secreted protein associated with a variety of malignancies. Our study focused on the expression and mechanism of LRG1 in ccRCC based on data from The Cancer Genome Atlas (TCGA) and provided primary verification including LRG1 expression detection, LRG1 gene methylation detection, and downstream signaling detection. We found that LRG1 was overexpressed in ccRCC kidney tissue samples, and the methylation level of LRG1 gene was significantly decreased in ccRCC. Moreover, the expression of LRG1 was negatively related to patient survival. Based on our previous study and the verification reported in this article, we propose that demethylation-induced overexpression of LRG1 is likely to accelerate ccRCC progression via the TGF-β pathway.

Association of mutations in chromatin modifiers with poor survival in clear cell renal cell carcinoma: Analysis of the Cancer Genome Atlas Project.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 360-360 ◽  
Author(s):  
A. Ari Hakimi ◽  
Irina Ostrovnaya ◽  
Martin Henner Voss ◽  
Robert John Motzer ◽  
Paul Russo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Competing Risk ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Epigenetic Modifiers ◽  
Cancer Genome Atlas ◽  
Genome Atlas

360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p<0.0001 HR 4.03 [2.1-7.9]). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. Conclusions: BAP1, SETD2 and KDM5C mutations are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.

scholarly journals A Novel Prognostic Model for Clear Cell Renal Cell Carcinoma with Differentially Expressed Immune-related lncRNA Pairs Based on the Cancer Genome Atlas

2021 ◽  
Author(s):  
Chen Zhao ◽  
Kewei Xiong ◽  
Fengming Liu ◽  
Xiangpan Li
Keyword(s):  
Renal Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Model ◽  
Cox Regression ◽  
Clear Cell ◽  
Risk Group ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Objective: To construct a novel prognostic model of immune-related lncRNA (irlncRNA) pairs in clear cell renal cell carcinoma (ccRCC). Methods: RNA-seq and clinical data were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed irlncRNAs (DEirlncRNAs) were obtained by co-expression strategy with immune genes. A 0-1 matrix was constructed according to DEirlncRNAs relevant expression levels. Univariate cox regression was used to select potential target pairs. Lasso regression with cross validation and multivariate cox regression were carried out to extract the final biomarker pairs for risk score calculation. Through calculating the optimal cutoff of AUCs, patients were divided into high and low risk group. Model validation was conducted by independent prognostic analysis, survival analysis, tumor-infiltrating and chemosensitivity analysis. Results: A total of 42 DEirlncRNAs were identified and 12 target pairs were included to construct the final model. The risk score were both significantly different according to univariate (p<0.001, HR=1.391, 95%CI [1.313–1.475]) and multivariate cox regression (p<0.001, HR=1.3104, 95%CI [1.227-1.399]). The AUC reached 0.765 at 1-year, 0.724 at 3-year and 0.785 at 5-year. Patients in the high-risk group had significantly poor survival, higher level of CD8+T infiltration, lower drug sensitivity of sunitinib and temsirolimus but higher sensitivity of lapatinib and pazopanib.Conclusion: The novel prognostic model constructed by paring irlncRNAs showed an effective clinical prediction in ccRCC patients.

scholarly journals Molecular Insights into the Classification of Luminal Breast Cancers: The Genomic Heterogeneity of Progesterone-Negative Tumors

2019 ◽  
Vol 20 (3) ◽  
pp. 510 ◽  
Author(s):  
Gianluca Lopez ◽  
Jole Costanza ◽  
Matteo Colleoni ◽  
Laura Fontana ◽  
Stefano Ferrero ◽  
...  
Keyword(s):  
Cancer Genomics ◽  
Molecular Taxonomy ◽  
The Cancer Genome Atlas ◽  
Rank Test ◽  
Breast Cancers ◽  
Cancer Genes ◽  
Kaplan Meier ◽  
Er Positive ◽  
Cancer Genome Atlas ◽  
Student’S T

Estrogen receptor (ER)-positive progesterone receptor (PR)-negative breast cancers are infrequent but clinically challenging. Despite the volume of genomic data available on these tumors, their biology remains poorly understood. Here, we aimed to identify clinically relevant subclasses of ER+/PR− breast cancers based on their mutational landscape. The Cancer Genomics Data Server was interrogated for mutational and clinical data of all ER+ breast cancers with information on PR status from The Cancer Genome Atlas (TCGA), Memorial Sloan Kettering (MSK), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) projects. Clustering analysis was performed using gplots, ggplot2, and ComplexHeatmap packages. Comparisons between groups were performed using the Student’s t-test and the test of Equal or Given Proportions. Survival curves were built according to the Kaplan–Meier method; differences in survival were assessed with the log-rank test. A total of 3570 ER+ breast cancers (PR− n = 959, 27%; PR+ n = 2611, 73%) were analyzed. Mutations in well-known cancer genes such as TP53, GATA3, CDH1, HER2, CDH1, and BRAF were private to or enriched for in PR− tumors. Mutual exclusivity analysis revealed the presence of four molecular clusters with significantly different prognosis on the basis of PIK3CA and TP53 status. ER+/PR− breast cancers are genetically heterogeneous and encompass a variety of distinct entities in terms of prognostic and predictive information.

scholarly journals CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression

2020 ◽  
Vol 21 (16) ◽  
pp. 5939
Author(s):  
Jiatong Xu ◽  
Songbiao Zhu ◽  
Lina Xu ◽  
Xiaohui Liu ◽  
Wenxi Ding ◽  
...  
Keyword(s):  
Cell Migration ◽  
Mitochondrial Biogenesis ◽  
Transmembrane Protein ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Amino Acid Transporters ◽  
Cell Renal Cell Carcinoma ◽  
Associated Proteins ◽  
Cancer Genome Atlas

Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC). The catalytic mechanisms of CA9 are well defined, but its roles in mediating cell migration/invasion and survival in ccRCC remain to be determined. Here, we confirmed that the mRNA expression of CA9 in ccRCC was significantly higher than that in para-carcinoma tissues from analysis of the datasets in The Cancer Genome Atlas. CA9 knockdown upregulated oxidative phosphorylation-associated proteins and increased mitochondrial biogenesis, resulting in the reversal of the Warburg phenotype and the inhibition of cell growth. Our study revealed that CA9 knockdown upregulated mitochondrial arginase 2 (ARG2), leading to the accumulation of putrescine, which suppressed ccRCC proliferation. Surfaceomics analysis revealed that CA9 knockdown downregulated proteins associated with extracellular matrix (ECM)—receptor interaction and cell adhesion, resulting in decreased cell migration. CA9 silencing also downregulated amino acid transporters, leading to reduced cellular amino acids. Collectively, our data show that CA9 knockdown suppresses proliferation via metabolic reprogramming and reduced cell migration, reaffirming that CA9 is a potential therapeutic target for ccRCC treatment.

scholarly journals The long noncoding RNA urothelial carcinoma-associated 1 overexpression as a poor prognostic biomarker in clear cell renal cell carcinoma

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769837 ◽  
Author(s):  
Yang Wang ◽  
Wen Gao ◽  
Jiali Xu ◽  
Yizhi Zhu ◽  
Lingxiang Liu
Keyword(s):  
Renal Cell Carcinoma ◽  
Urothelial Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Noncoding Rna ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Long noncoding RNA urothelial carcinoma-associated 1 has previously played important roles in cancer. However, its role is still unknown in clear cell renal cell carcinoma. We utilized the most recent molecular and clinical data of clear cell renal cell carcinoma from The Cancer Genome Atlas project, and the relationship between urothelial carcinoma-associated 1 expression and the clinicopathological features was analyzed. Our results indicated that urothelial carcinoma-associated 1 overexpression was associated with male ( p = 0.003), wild-type PBRM1 ( p = 0.021), and BAP1 mutation ( p = 0.022) in clear cell renal cell carcinoma, although lower expression was found in tumors compared with normal controls, validated in tumor tissues from The Cancer Genome Atlas and 21 clear cell renal cell carcinoma patients at our hospital. Moreover, urothelial carcinoma-associated 1 overexpression indicated poor prognosis independently (Hazard Ratio [HR]: 1.92, p = 0.000) in clear cell renal cell carcinoma; it might be a potential detrimental gene considered as a predictive biomarker involved in clear cell renal cell carcinoma.

scholarly journals Systematic analysis of aberrances of ferroptosis reveals its potential functional roles in cancer

2019 ◽  
Author(s):  
Zekun Liu ◽  
Qi Zhao ◽  
Zhi-Xiang Zuo ◽  
Shu-Qiang Yuan ◽  
Kai Yu ◽  
...  
Keyword(s):  
The Cancer Genome Atlas ◽  
Copy Number Alterations ◽  
Aberrant Expression ◽  
Systematic Analysis ◽  
Functional Roles ◽  
Normal Tissues ◽  
Potential Index ◽  
Cancer Genome Atlas ◽  
Regulator Genes ◽  
Worse Prognosis

SummaryFerroptosis is a type of cell death that related to cancer, however, the characteristics of ferroptosis in cancers are still uncertain. Based on the data in The Cancer Genome Atlas, we found that most ferroptosis regulator genes (FRGs) were differentially expressed in tumors, copy number alterations (CNA) and DNA methylation contributed to their aberrant expression. We established the ferroptosis potential index (FPI) to reveal the functional roles of ferroptosis and noticed that the FPI was higher in tumors than in normal tissues in most cancers, and was associated with subtypes and clinical features. The FPI was negatively correlated with several metabolism pathways but positively associated with several important metastasis-related pathways and immune-related pathways. Higher FPI predicted worse prognosis in several tumors, while FPI and FRGs impacted drug sensitivity. Our study presents a systematical analysis of ferroptosis and its regulatory genes, and highlights the potential of ferroptosis-based cancer therapy.

scholarly journals Caspase 4 Overexpression in Clear Cell Renal Cell Carcinoma and Its Prognostic Role

2020 ◽  
Author(s):  
Lingfeng Meng ◽  
Zijian Tian ◽  
Xingbo Long ◽  
Tongxiang Diao ◽  
Maolin Hu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Abstract Background: Caspase 4 (CASP4) dysregulation is related to the occurrence, development, and outcome of many malignant tumors, but its role in clear cell renal cell carcinoma (ccRCC) is unclear. This study was conducted to investigate the expression level of CASP4 in tumor tissues and its relationship with clinical prognosis of patients with ccRCC. Methods: First, the Oncomine and The Cancer Genome Atlas databases were used to determine CASP4 mRNA expression in ccRCC and its association with ccRCC prognosis. We then performed immunohistochemical staining and evaluation of 30 paired ccRCC and adjacent normal tissues to confirm these results. The correlation between CASP4 expression and ccRCC prognosis was evaluated using Kaplan-Meier analysis, and related genes and pathways were obtained from The Cancer Genome Atlas database by gene set enrichment analysis and gene set variation analysis. Finally, we explored the co-expression of genes with CASP4 in ccRCC. Results: CASP4 mRNA expression in ccRCC was significantly higher than that in normal tissues (p < 0.001). Kaplan-Meier analysis showed that the overall survival of patients with ccRCC showing high CASP4 expression was significantly reduced (p < 0.001). We then used external datasets (Gene Expression Omnibus database and patients from our center) to verify the level of CASP4 expression and survival differences (all p < 0.05). We also found that differential expression levels of CASP4 were correlated with pathological grade and clinical TNM stage (all p < 0.05). Conclusions: Overall, our study shows that CASP4 is highly expressed in ccRCC and is an important factor affecting prognosis. Thus, CASP4 may be a potential prognostic biomarker of ccRCC.

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