DNA Damage Repair (DDR) gene and VHL concurrent alterations in advanced clear cell Renal Cell Carcinoma (ccRCC) are association with good progression free survival with tyrosine kinase inhibitor therapy

2021 ◽  
Vol 79 ◽  
pp. S742
Author(s):  
W. Zhai ◽  
J. Wang ◽  
N. He ◽  
J. Zhou ◽  
J. Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Damage Repair ◽  
Tyrosine Kinase Inhibitor Therapy

scholarly journals NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

2022 ◽  
Author(s):  
Daniel Serie ◽  
Amanda A Myers ◽  
Daniela A Haehn ◽  
Alexander Parker ◽  
Essa Bajalia ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Differential Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Progression Free Survival ◽  
P Value ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Kaplan Meier

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001). Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

scholarly journals The Clinical Significance of DNA Damage Repair Signatures in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Ergang Guo ◽  
Cheng Wu ◽  
Jun Ming ◽  
Wei Zhang ◽  
Linli Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Dna Repair Genes ◽  
Cell Renal Cell Carcinoma ◽  
Damage Repair ◽  
Repair Genes

DNA damage repair plays an important role in cancer’s initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.

scholarly journals Predictors of Progression-Free Survival and Overall Survival in Metastatic Non-Clear Cell Renal Cell Carcinoma: A Single-Center Experience

2019 ◽  
Vol 10 (2) ◽  
pp. 101-111 ◽  
Author(s):  
Sasanka Kumar Barua ◽  
Yashasvi Singh ◽  
Saumar Jyoti Baruah ◽  
Rajeev T.P. ◽  
Puskal K. Bagchi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Single Center ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Single Center Experience

scholarly journals Predicting Clear Cell Renal Cell Carcinoma Survival Using Kurtosis of Cytoplasm in the Hematoxylin Channel from Histology Slides

2022 ◽  
Vol 2022 ◽  
pp. 1-9
Author(s):  
Jun Wang ◽  
Jianhui Chen ◽  
Liren Jiang ◽  
Qi Wu ◽  
Dawei Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Survival Analysis ◽  
Cell Carcinoma ◽  
Survival Time ◽  
Renal Cell ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival

Purpose. Grade-dependent decrease of lipid storage in clear cell renal cell carcinoma (ccRCC) leads to morphology changes in HE sections. This study investigated the role of cytoplasmic features in frozen sections of ccRCC on prognosis using the digital pathology approach. Methods. We established an automatic pipeline that performed tumor region selection, stain vector normalization, nuclei segmentation, and feature extraction based on the pathologic data from Shanghai General Hospital and The Cancer Genome Atlas database. Extracted features were subjected to survival analysis. Results. Kurtosis of the cytoplasm in the hematoxylin channel was correlated with progression-free survival (HR 0.10, 95% CI: 0.04–0.24, p = 6.52 ∗ 10 − 7 ) and overall survival (HR 0.11, 95% CI: 0.05–0.31, p = 1.72 ∗ 10 − 5 ) in ccRCC, which outperformed other texture features in this analysis. Multivariate Cox regression analysis revealed that low kurtosis of cytoplasm in the hematoxylin channel was an independent predictor for a shorter progression-free survival time ( p = 0.044 ) and overall survival time (p = 0.01). Kaplan–Meier survival analysis of progression-free survival and overall survival also showed a significantly worse prognosis in patients with low kurtosis of the cytoplasm in the hematoxylin channel (both p < 0.0001 ). Lower kurtosis of cytoplasm in the hematoxylin channel was associated with higher pathologic grade, less cholesterol ester, and more mitochondrial DNA content. Conclusion. Kurtosis of the cytoplasm in the hematoxylin channel predicts survival in clear cell renal cell carcinoma.

Comprehensive Analysis of DNA Damage Repair Genes and Identification of RAD54L as an Immunological and Prognostic Biomarker in Clear Cell Renal Cell Carcinoma and Other Cancers

2021 ◽  
Author(s):  
Song Wang ◽  
Zitong Yang ◽  
Jiahe Yi ◽  
Zixiang Liu ◽  
Jiangfeng Li ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Tumor Microenvironment ◽  
Renal Cell ◽  
Clear Cell ◽  
Prognostic Biomarker ◽  
Cell Renal Cell Carcinoma ◽  
Qrt Pcr ◽  
Damage Repair ◽  
Worse Prognosis

Abstract Background: DNA damage repair (DDR) plays a pivotal role in the tumorigenesis and progression of multiple cancers, including clear cell renal cell carcinoma (ccRCC), and immunotherapy is galvanizing research on ccRCC, while the interactions between DDR and tumor microenvironment (TME) in ccRCC still remain elusive. Methods: The expression, mutation and clinical data were downloaded from public datasets in TCGA, GTEx and human protein atlas (HPA) database. Consensus clustering analysis was used to cluster subtypes based upon the expression of DDR genes. Cox regression analysis was adopted to conduct survival analysis, and qRT-PCR method was used to verify the expression of RAD54L in ccRCC samples. GSEA was employed to explore potential enriched KEGG pathways. CIBERSORT, ssGSEA and xCell algorithms were used to evaluate the tumor microenvironment (TME).Results: Two subtypes were identified according to the expression of DDR genes in ccRCC. Subtype1 was correlated with increased proportion of higher-grade tumors, worse prognosis and lower PD-L1 expression compared to subtype2. Distinct TME was also noted between two subtypes. GSEA revealed that the TGF-β signaling pathway was significantly enriched in subtype1. RAD54L was subsequently determined as a potential immune-related DDR gene, which was positively associated with PD-L1 expression and its elevated expression predicted unfavorable prognosis in ccRCC. qRT-PCR also verified the overexpression of RAD54L in ccRCC samples. Additionally, a systematic analysis involving 33 cancer types demonstrated that RAD54L was remarkably upregulated and its overexpression tightly linked to worse prognosis in multiple cancers. Moreover, both xCell and ssGSEA algorithm showed the strong associations between RAD54L expression and immune infiltration in more than 30 cancers. Conclusions: DDR is implicated in regulating TME of ccRCC, and RAD54L is a potential immunological and prognostic biomarker in multiple types of cancer, including ccRCC.

Prognostic and predictive role of intra-tumoral CXCR1 expression in patients receiving tyrosine kinase inhibitors for metastatic clear-cell renal cell carcinoma

2021 ◽  
pp. 205141582110122
Author(s):  
Sridhar Panaiyadiyan ◽  
Brusabhanu Nayak ◽  
Prabhjot Singh ◽  
Seema Kaushal ◽  
Subhradip Karmakar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival

Objective: We aimed to evaluate the role of intra-tumoral CXCR1 expression in predicting prognosis and treatment response in metastatic clear-cell renal cell carcinoma patients receiving tyrosine kinase inhibitors. Materials and methods: Patients with metastatic clear-cell renal cell carcinoma presented between February 2018–December 2019 were studied for the CXCR1 expression in tumor tissues before starting tyrosine kinase inhibitors. Primary outcome measure was progression-free survival. Secondary outcome measures included overall survival and prediction of treatment response. Results: The study included 35 patients with a mean age of 53.6±9.6 years. At a mean follow-up of 12.2±4.1 months, 17 (48.6%) patients had disease progression including eight (22.9%) deaths. Patients with high CXCR1 expression, compared to those with low CXCR1 expression, had a significantly shorter 12-month progression-free survival (35.4% vs 77.9%, p=0.01) and an insignificant impact on 12-month overall survival. The CXCR1 expression scores significantly differed between patients with progressive and nonprogressive disease (20.1 vs 15.1, p=0.01) and patients with high CXCR1 expression had a reduced benefit from tyrosine kinase inhibitors. The multivariate Cox regression analysis showed CXCR1 expression as a significant predictor of progression-free survival. Conclusion: High intra-tumoral CXCR1 expression before tyrosine kinase inhibitors can be an independent prognostic factor for progression-free survival and predictor of reduced benefit in patients with metastatic clear-cell renal cell carcinoma. Level of evidence: Level 2b.

Genomic instability and DNA damage repair in clear cell renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4581-4581
Author(s):  
Patrick Glen Pilie ◽  
Lijun Zhou ◽  
Pan Tong ◽  
Surena F. Matin ◽  
Kanishka Sircar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Cell Carcinoma ◽  
Genomic Instability ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Cell Renal Cell Carcinoma ◽  
Mutator Phenotype ◽  
Damage Repair

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.

199 PHD3 expression is a predictor of progression-free survival in clear cell renal cell carcinoma

2012 ◽  
Vol 11 (1) ◽  
pp. e199-e199a
Author(s):  
T. Tanaka ◽  
H. Kitamura ◽  
T. Torigoe ◽  
Y. Hirohashi ◽  
N. Masumori ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival

Modest efficacy of nivolumab plus ipilimumab in patients with papillary renal cell carcinoma

2020 ◽  
Author(s):  
Hidekazu Tachibana ◽  
Tsunenori Kondo ◽  
Hiroki Ishihara ◽  
Hironori Fukuda ◽  
Kazuhiko Yoshida ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Response Rate ◽  
Clear Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Papillary Renal Cell Carcinoma ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival

Abstract Purpose Combined immunotherapy of nivolumab plus ipilimumab for intermediate- and poor-risk metastatic clear cell renal cell carcinoma showed prolonged progression-free survival and high objective response rate in a randomized phase III clinical trial. However, the efficacy of this treatment for papillary renal cell carcinoma remains unclear. In the present study, we analysed the efficacy of nivolumab plus ipilimumab therapy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. Materials and Methods This is a retrospective study of 30 patients with metastatic renal cell carcinoma who received nivolumab and ipilimumab as first-line therapy between December 2015 and May 2020. The objective response rate, progression-free survival and toxicity were compared between the two groups (clear cell renal cell carcinoma and papillary renal cell carcinoma). Results Out of 30 patients, 7 and 23 were diagnosed with papillary renal cell carcinoma and clear cell renal cell carcinoma, respectively. With a median follow-up of 7.2 months, the median progression-free survival was significantly shorter in papillary renal cell carcinoma than in clear cell renal cell carcinoma (2.4 vs. 28.1 months, P = 0.014). Of the seven patients with papillary renal cell carcinoma, one had partial response, one had stable disease and five had progressive disease, resulting in an objective response rate of 14.2%, which was lower compared to that of clear cell renal cell carcinoma (14.2 vs. 52.1%, P = 0.06). Discontinuation due to toxicity was not observed with papillary renal cell carcinoma, meanwhile 60.8% of patient with clear cell renal cell carcinoma discontinued treatment due to toxicity. Conclusion Nivolumab plus ipilimumab had modest efficacy for papillary renal cell carcinoma compared with that for clear cell renal cell carcinoma. Nivolumab plus ipilimumab remains an option for a limited number of patients with intermediate- or poor-risk papillary renal cell carcinoma.

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