scholarly journals Comprehensive Analysis of BAP1 Somatic Mutation in Clear Cell Renal Cell Carcinoma to Explore Potential Mechanisms in Silico

2018 ◽  
Vol 9 (22) ◽  
pp. 4108-4116 ◽  
Author(s):  
Shengming Jin ◽  
Junlong Wu ◽  
Yao Zhu ◽  
Weijie Gu ◽  
Fangning Wan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Somatic Mutation ◽  
In Silico ◽  
Renal Cell ◽  
Clear Cell ◽  
Comprehensive Analysis ◽  
Cell Renal Cell Carcinoma

Homologous repair deficiency in VHL-mutated clear cell renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 585-585 ◽  
Author(s):  
Patrick Glen Pilie ◽  
Lijun Zhou ◽  
Christine B Peterson ◽  
Yang Peng ◽  
Guang Peng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Proteomic Analysis ◽  
In Silico ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Gene Signature ◽  
Cell Renal Cell Carcinoma ◽  
Tumor Stages

585 Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive to DNA damaging agents. We hypothesized that biallelic VHL loss is sufficient to cause HR deficiency (HRD) and that early stage ccRCC is more likely to display HRD than late stage disease. Methods: We performed whole-exome (WES) sequencing of 15 small ccRCC tumors to assess for mutational burden, mutational signature, and cancer-related driver gene mutations. We performed in silico genomic, transcriptomic, and proteomic analysis of tumors in KIRC TCGA to assess for HRD. Finally, we assessed HR efficiency as a product of biallelic VHL loss in engineered cell line models. Results: 15/15 early stage ccRCC had VHL mutations, approximately 100 additional mutations per tumor, but no common mutations found in KIRC TCGA. In silico analysis showed 67% of KIRC TCGA displayed HRD gene signature, and was significantly higher in stage I disease (p = 2.21e-08). Patients with VHL-mutated tumors are more commonly HRD than HR intact (HRI) (p = 0.03), with frameshift/nonsense variants in VHL more likely to result in HRD than missense variants (p = 0.02). Multivariate analysis showed HRD predicted for better overall survival compared to HRI (p < 0.0001). Proteomic analysis of KIRC TCGA revealed HRI samples had significantly higher protein expression of Rad51 and RAPTOR when compared to HRD samples. Lastly, etoposide-treated MEF Vhl-/- cell lines displayed reduced HR efficiency when compared to Vhl intact controls. Conclusions: Biallelic loss of VHL is sufficient to cause HRD. HRD gene signature predicts for significantly better OS in ccRCC patients, and early stage ccRCC is more likely to be HRD. mTOR/PI3K signaling pathway proteins are differentially expressed in HRI patient samples from TCGA compared to HRD, suggesting a possible role for these oncogenes driving a HRI phenotype. Treatment strategies combining PARP inhibitors with PI3K/mTOR inhibitors should be tested in advanced VHL-mutated ccRCC.

scholarly journals Comprehensive analysis of somatic copy number alterations in clear cell renal cell carcinoma

2020 ◽  
Vol 59 (4) ◽  
pp. 412-424 ◽  
Author(s):  
Takashi Tsuyukubo ◽  
Kazuyuki Ishida ◽  
Mitsumasa Osakabe ◽  
Ei Shiomi ◽  
Renpei Kato ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Copy Number ◽  
Clear Cell ◽  
Comprehensive Analysis ◽  
Copy Number Alterations ◽  
Cell Renal Cell Carcinoma ◽  
Somatic Copy Number Alterations

Comprehensive Analysis of Survival Outcomes in Non–Clear Cell Renal Cell Carcinoma Patients Treated in Clinical Trials

2017 ◽  
Vol 15 (6) ◽  
pp. 652-660.e1 ◽  
Author(s):  
Guillermo de Velasco ◽  
Rana R. McKay ◽  
Xun Lin ◽  
Raphel B. Moreira ◽  
Ronit Simantov ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Comprehensive Analysis ◽  
Survival Outcomes ◽  
Cell Renal Cell Carcinoma
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