Proteomic stratification of clear cell renal cell carcinoma utilizing The Cancer Genome Atlas (TCGA) with external validation.

406 Background: Proteomics represents the ultimate convergence of DNA and expression alterations. We therefore sought to leverage TCGA reverse phase protein array (RPPA) data with an independent proteomic platform to identify druggable targets and pathways associated with prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Unsupervised hierarchical consensus clustering was performed and differentially expressed proteins were identified for pathway analysis. Associations with clinicogenomic factors were assessed and Cox proportional hazards models were performed for disease-specific survival (DSS). Results: RPPA clustering of 324 patients from the ccRCC TCGA revealed 5 robust clusters characterized by alterations in specific pathways and divergent prognoses. Cluster 1 was characterized by poor DSS, decreased expression of receptor tyrosine kinases (RTK) and upregulation of the mTOR pathway. It was also associated with mTOR pathway genomic alterations, sarcomatoid histology and the ccb prognostic mRNA signature (all p<0.001). Cluster 2 was characterized by increased expression of RTKs and interestingly, had upregulation of the mTOR pathway with excellent DSS. After accounting for stage and grade, cluster designation remained independently associated with DSS (HR 0.23 for cluster 2, 95% CI 0.08-0.68; p=0.008). External validation was performed on a separate cohort of 189 patients with a different quantitative proteomics platform. A panel of phosphoproteins (pHER1, pHER2, pHER3, pSHC, pMEK, pAKT), highly discriminant between the most divergent RPPA clusters (1 and 2) was evaluated. Those at the highest quartile of activation in > 3 proteins were associated with improved DSS (HR 0.19, 95% CI 0.05-0.082; p=0.03). Patients with mTOR pathway activation segregated to those with coincident RTK activation (n=83) and those without (n=13). Conclusions: We have identified and validated proteomic signatures which cluster ccRCC patients into 5 prognostic groups. Furthermore, two distinct mTOR-activated clusters—one with high RTK activity and one with increased mTOR pathway genomic alterations were revealed, which may have prognostic and therapeutic implications.

Download Full-text

MP35-01 PROTEOMIC STRATIFICATION OF CLEAR CELL RENAL CELL CARCINOMA UTILIZING THE CANCER GENOME ATLAS (TCGA) WITH EXTERNAL VALIDATION

The Journal of Urology ◽

10.1016/j.juro.2015.02.1102 ◽

2015 ◽

Vol 193 (4S) ◽

Author(s):

Samuel Kaffenberger ◽

Giovanni Ciriello ◽

Andrew Winer ◽

Martin Voss ◽

Jodi Maranchie ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

External Validation ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas

Download Full-text

Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma

BioMed Research International ◽

10.1155/2018/9303486 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Kang Yang ◽

Xiao-fan Lu ◽

Peng-cheng Luo ◽

Jie Zhang

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Expression Profiles ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Cerna Network

Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis.

Download Full-text

Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma

Kidney Cancer ◽

10.3233/kca-160003 ◽

2017 ◽

Vol 1 (1) ◽

pp. 49-56 ◽

Cited By ~ 16

Author(s):

M.I. Carlo ◽

B. Manley ◽

S. Patil ◽

K.M. Woo ◽

D.T. Coskey ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Genomic Alterations ◽

Cell Renal Cell Carcinoma

Download Full-text

A novel 10 glycolysis-related genes signature could predict overall survival for clear cell renal cell carcinoma

BMC Cancer ◽

10.1186/s12885-021-08111-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qianwei Xing ◽

Tengyue Zeng ◽

Shouyong Liu ◽

Hong Cheng ◽

Limin Ma ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Cox Regression ◽

Clear Cell ◽

Low Risk ◽

The Cancer Genome Atlas ◽

Regression Analyses ◽

Cell Renal Cell Carcinoma

Abstract Background The role of glycolysis in tumorigenesis has received increasing attention and multiple glycolysis-related genes (GRGs) have been proven to be associated with tumor metastasis. Hence, we aimed to construct a prognostic signature based on GRGs for clear cell renal cell carcinoma (ccRCC) and to explore its relationships with immune infiltration. Methods Clinical information and RNA-sequencing data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) and ArrayExpress datasets. Key GRGs were finally selected through univariate COX, LASSO and multivariate COX regression analyses. External and internal verifications were further carried out to verify our established signature. Results Finally, 10 GRGs including ANKZF1, CD44, CHST6, HS6ST2, IDUA, KIF20A, NDST3, PLOD2, VCAN, FBP1 were selected out and utilized to establish a novel signature. Compared with the low-risk group, ccRCC patients in high-risk groups showed a lower overall survival (OS) rate (P = 5.548Ee-13) and its AUCs based on our established signature were all above 0.70. Univariate/multivariate Cox regression analyses further proved that this signature could serve as an independent prognostic factor (all P < 0.05). Moreover, prognostic nomograms were also created to find out the associations between the established signature, clinical factors and OS for ccRCC in both the TCGA and ArrayExpress cohorts. All results remained consistent after external and internal verification. Besides, nine out of 21 tumor-infiltrating immune cells (TIICs) were highly related to high- and low- risk ccRCC patients stratified by our established signature. Conclusions A novel signature based on 10 prognostic GRGs was successfully established and verified externally and internally for predicting OS of ccRCC, helping clinicians better and more intuitively predict patients’ survival.

Download Full-text

Long Non-Coding RNA LINC02747 Promotes the Proliferation of Clear Cell Renal Cell Carcinoma by Inhibiting miR-608 and Activating TFE3

Frontiers in Oncology ◽

10.3389/fonc.2020.573789 ◽

2020 ◽

Vol 10 ◽

Author(s):

Xiang Ju ◽

Yangyang Sun ◽

Feng Zhang ◽

Xiaohui Wei ◽

Zhenguo Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Histological Grade ◽

Rapid Development ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma

With the rapid development of biotechnology, long noncoding RNAs (lncRNAs) have exhibited good application prospects in the treatment of cancer, and they may become new treatment targets for cancer. This study aimed to explore lncRNAs in clear cell renal cell carcinoma (ccRCC). Differentially expressed lncRNAs in 54 pairs of ccRCC tissues and para-carcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA), and the most significant lncRNAs were selected and verified in ccRCC tissues. We found that lncRNA LINC02747 was highly expressed in ccRCC (P < 0.001) and was closely related to high TNM stage (P = 0.006) and histological grade (P = 0.004) and poor prognosis of patients (P < 0.001). In vivo and in vitro experiments confirmed that LINC02747 could promote the proliferation of ccRCC cells. We also found that LINC02747 regulated the proliferation of RCC cells by adsorbing miR-608. Subsequent mechanistic research showed that miR-608 is downregulated in ccRCC (P < 0.001), and overexpression of miR-608 inbibited the proliferation of RCC cells. Moreover, we found that TFE3 is a direct target gene of miR-608. MiR-608 regulated the proliferation of RCC cells by inhibiting TFE3. In conclusion, LINC02747 upregulates the expression of TFE3 by adsorbing miR-608, ultimately promoting the proliferation of ccRCC cells. The above findings indicate that LINC02747 acts as an oncogene in ccRCC and may be developed as a molecular marker for the diagnosis and prognosis of ccRCC. The LINC02747/miR-608/TFE3 pathway may become a new therapeutic target for ccRCC.

Download Full-text

Long Noncoding RNA HOTTIP Serves as an Independent Predictive Biomarker for the Prognosis of Patients with Clear Cell Renal Cell Carcinoma

International Journal of Genomics ◽

10.1155/2020/4301634 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Zhanxin Liu ◽

Zichun Wang ◽

Xiaoxiong Wang ◽

Meisong Lu ◽

Guang Chen

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Noncoding Rna ◽

Clear Cell ◽

Clinical Stage ◽

Predictive Biomarker ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Advanced Clinical Stage

Several studies have indicated that HOXA transcript at the distal tip (HOTTIP) play important roles in the tumorigenesis and development of various cancers. We aim to investigate the expression and prognostic value of HOTTIP in clear cell renal cell carcinoma (ccRCC). A systematic review of PubMed, Embase, Medline, and Web of Science databases was performed to select eligible literatures relevant to the correlation between HOTTIP expression and clinical outcome of different cancers. The association between the HOTTIP level and overall survival (OS), lymph node metastasis (LNM), or clinical stage was subsequently analyzed. Survival analyses were performed in a large cohort of more than 500 patients with ccRCC from The Cancer Genome Atlas (TCGA) using bioinformatic methods. Seventeen studies with a total of 1594 patients with thirteen kinds of carcinomas were included in this analysis. The result showed that high HOTTIP expression could predict worse outcome in cancer patients, with the pooled hazard ratio (HR) of 2.34 (95% confidence interval (CI) 1.96–2.79, p<0.0001). The result also showed that elevated HOTTIP expression was correlated with more LNM (OR=2.61, 95% CI 1.91-3.58, p<0.0001) and advanced clinical stage (OR=3.57, 95% CI 2.58-4.93, p<0.0001). We further validated that ccRCC patients with higher HOTTIP expression tend to have unsatisfactory outcomes both in the entire TCGA dataset and different clinical stratums, like age, grade, and stage. The tumor of those patients was associated with a larger size, easier to metastasis, advanced clinical stage, and a higher pathological grade. These findings suggested that increased HOTTIP expression might act as a novel prognostic marker for ccRCC patients.

Download Full-text

8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness

BMC Urology ◽

10.1186/s12894-020-00745-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jeanette E. Eckel-Passow ◽

Huihuang Yan ◽

Matthew L. Kosel ◽

Daniel Serie ◽

Paul A. Decker ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Target Genes ◽

Clear Cell ◽

The Cancer Genome Atlas ◽

Cell Renal Cell Carcinoma ◽

Mutation Status ◽

Germline Variants ◽

Tumor Genetics

Abstract Background The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown. Methods We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. Results The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. Conclusions These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

Download Full-text