scholarly journals A Proteogenomic Atlas of Clear Cell Renal Cell Carcinoma in a Chinese Population

2021 ◽  
Author(s):  
Chen Ding ◽  
Yuan-Yuan Qu ◽  
Jinwen Feng ◽  
Xiaohui Wu ◽  
Lin Bai ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Large Scale ◽  
Clear Cell ◽  
Genomic Analysis ◽  
Genomic Alterations ◽  
Cell Renal Cell Carcinoma ◽  
Genetic Features ◽  
One Carbon Metabolism

Abstract Renal cell carcinoma (RCC) is among the top 10 malignant carcinomas1. Clear cell (cc)RCC, accounting for ~ 75% of RCC cases, is an aggressive histological RCC subtype. In the last decade, large-scale multiomics studies have profoundly enhanced our understanding of this disease2,3. However, despite the differences of genomic alterations between Western and Eastern ccRCC4,5, these studies mostly focused on patients in Western populations. Here we conducted a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. Genomic analysis revealed unique genetic features of Chinese ccRCC and distinct mutation patterns associated with copy number alterations. Based on proteomic profiles, ccRCC showed extensive metabolic dysregulation, especially in one-carbon metabolism. We classified ccRCC into three subtypes (GP1–3), among which the most aggressive GP1 exhibited dominant immune response, metastasis, and metabolic imbalance, linking the proteomic features, genomic alterations, and clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT) and NNMT mediated protein homocysteinylation were identified as a poor prognosis indicator and a drug target for GP1, respectively. We demonstrated that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes tumor growth in ccRCC. Treatment of N-acetyl-cysteine (NAC), an inhibitor of homocysteinylation, markedly reduced the NNMT overexpression induced radioresistance of tumor cells. This study provided valuable insights into the biological underpinnings and prognosis assessment of ccRCC, revealing a targetable metabolic vulnerability.

Exploiting Synthetic Lethal Network for Precision Treatment of Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Zhicheng Liu ◽  
Dongxu Lin ◽  
Linmeng Zhang ◽  
Chen Yang ◽  
Bin Guo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Large Scale ◽  
Target Genes ◽  
Clear Cell ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Treatment Modalities ◽  
Cell Renal Cell Carcinoma

Abstract Background The emerging of targeted therapies has revolutionized the treatment modalities of advanced clear cell renal cell carcinoma (ccRCC) over the past fifteen years. However, lack of personalized treatment limits the development of effective clinical guidelines and improvement of patient prognosis. In this study, large-scale genomic profiles of ccRCC cohorts were exploited for conducting an integrative analysis. Method Based on synthetic lethality (SL), a concept that simultaneous losses of two genes cause cell death while a single loss does not, we sought to develop a computational pipeline to infer potential SL partners of ccRCC. Drug response prediction were received from three pharmacological databases to select agents which are likely to be effective in precisely treating patients with target gene mutation. Results We developed a credible method to identify SL pairs and determined a list of 72 candidate pairs which might be utilized to selectively eliminate tumors with genetic aberrations through SL partners of specific mutations. Further analysis identified BRD4 and PRKDC as novel medicine targets for patients with BAP1 mutations. After mapping these target genes to comprehensive drug datasets, two agents (BI-2536 and PI-103) were found to have considerable therapeutic potential in BAP1 mutant tumors. Conclusion Overall, our findings provide insight into the overview of ccRCC mutation patterns and offer novel opportunities for improving individualized cancer treatment.

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

Kidney Cancer ◽  
2017 ◽  
Vol 1 (1) ◽  
pp. 49-56 ◽  
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

617 GENOMIC ALTERATIONS ASSOCIATED WITH METASTASIS AND POOR PROGNOSIS IN CLEAR CELL RENAL CELL CARCINOMA

2010 ◽  
Vol 183 (4S) ◽  
Author(s):  
Jimsgene Sanjmyatav ◽  
Carsten Schwaenen ◽  
Sven Wessendorf ◽  
Markus Kreuz ◽  
Thomas Steiner ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Poor Prognosis ◽  
Clear Cell ◽  
Genomic Alterations ◽  
Cell Renal Cell Carcinoma

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

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 406-406
Author(s):  
Samuel D. Kaffenberger ◽  
Giovanni Ciriello ◽  
Andrew G. Winer ◽  
Martin Henner Voss ◽  
Jodi Kathleen Maranchie ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
External Validation ◽  
Mtor Pathway ◽  
The Cancer Genome Atlas ◽  
Genomic Alterations ◽  
Cell Renal Cell Carcinoma ◽  
Cluster 2

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.

Abstract 52: Identification of genomic alterations associated with metastasis in clear cell renal cell carcinoma

2014 ◽  
Author(s):  
Venkata J. Thodima ◽  
Banumathy Gowrishankar ◽  
Ana Molina ◽  
Murielle Georges ◽  
RSK Chaganti ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Genomic Alterations ◽  
Cell Renal Cell Carcinoma

scholarly journals The epigenetic landscape of clear-cell renal cell carcinoma

2015 ◽  
Vol 2 (3) ◽  
pp. 90-104 ◽  
Author(s):  
Katarzyna Kluzek ◽  
Hans Antonius Bluyssen ◽  
Joanna Wesoly
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Large Scale ◽  
Clear Cell ◽  
Kidney Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Chromosome 3P ◽  
Recurrent Mutations ◽  
Novel Therapeutic Strategies

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of all kidney tumors. During the last few years, epigenetics has emerged as an important mechanism in ccRCC pathogenesis. Recent reports, involving large-scale methylation and sequencing analyses, have identified genes frequently inactivated by promoter methylation and recurrent mutations in genes encoding chromatin regulatory proteins. Interestingly, three of detected genes (PBRM1, SETD2 and BAP1) are located on chromosome 3p, near the VHL gene, inactivated in over 80% ccRCC cases. This suggests that 3p alterations are an essential part of ccRCC pathogenesis. Moreover, most of the proteins encoded by these genes cooperate in histone H3 modifications. The aim of this review is to summarize the latest discoveries shedding light on deregulation of chromatin machinery in ccRCC. Newly described ccRCC-specific epigenetic alterations could potentially serve as novel diagnostic and prognostic biomarkers and become an object of novel therapeutic strategies.

Abstract 346: Integrative genomic analysis of sporadic clear cell renal cell carcinoma

2011 ◽  
Author(s):  
Vijay R. Dondeti ◽  
Bradley Wubbenhorst ◽  
Priti Lal ◽  
John D. Gordan ◽  
Kurt D'Andrea ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Genomic Analysis ◽  
Cell Renal Cell Carcinoma
Sign in / Sign up

Export Citation Format

Share Document