scholarly journals Spatial Distribution of Private Gene Mutations in Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2163
Author(s):  
Ariane L. Moore ◽  
Aashil A. Batavia ◽  
Jack Kuipers ◽  
Jochen Singer ◽  
Elodie Burcklen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Second Phase ◽  
Tumour Heterogeneity ◽  
Cell Renal Cell Carcinoma ◽  
Two Samples ◽  
Paired Tumour

Intra-tumour heterogeneity is the molecular hallmark of renal cancer, and the molecular tumour composition determines the treatment outcome of renal cancer patients. In renal cancer tumourigenesis, in general, different tumour clones evolve over time. We analysed intra-tumour heterogeneity and subclonal mutation patterns in 178 tumour samples obtained from 89 clear cell renal cell carcinoma patients. In an initial discovery phase, whole-exome and transcriptome sequencing data from paired tumour biopsies from 16 ccRCC patients were used to design a gene panel for follow-up analysis. In this second phase, 826 selected genes were targeted at deep coverage in an extended cohort of 89 patients for a detailed analysis of tumour heterogeneity. On average, we found 22 mutations per patient. Pairwise comparison of the two biopsies from the same tumour revealed that on average, 62% of the mutations in a patient were detected in one of the two samples. In addition to commonly mutated genes (VHL, PBRM1, SETD2 and BAP1), frequent subclonal mutations with low variant allele frequency (<10%) were observed in TP53 and in mucin coding genes MUC6, MUC16, and MUC3A. Of the 89 ccRCC tumours, 87 (~98%) harboured private mutations, occurring in only one of the paired tumour samples. Clonally exclusive pathway pairs were identified using the WES data set from 16 ccRCC patients. Our findings imply that shared and private mutations significantly contribute to the complexity of differential gene expression and pathway interaction and might explain the clonal evolution of different molecular renal cancer subgroups. Multi-regional sequencing is central for the identification of subclones within ccRCC.

Robustness of the 16-gene signature for prediction of recurrence-free interval in localized clear cell renal cell carcinoma.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 455-455
Author(s):  
Bernard J. Escudier ◽  
Serge Koscielny ◽  
Tara Maddala ◽  
Christer Svedman ◽  
Virginie Verkarre ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Signature ◽  
Stage I ◽  
Rt Pcr ◽  
Cell Renal Cell Carcinoma ◽  
Risk Of Recurrence

455 Background: The Renal Cancer assay is a clinically validated RT-PCR assay developed to estimate the risk of recurrence in stage I-III clear cell renal cell carcinoma (ccRCC) patients (pts) treated with nephrectomy. The assay measures expression of 16 genes that are combined to calculate the Recurrence Score result (RS). The RS is associated with recurrence, renal cancer-specific survival and overall survival (all p<0.001) (Escudier, ASCO 2014). The performance of the RS in clinically relevant subgroups, compared to the Leibovich score, and its within-patient variability was examined. Methods: The algorithm, endpoints, methods, and analysis plan were pre-specified prior to merging clinical and molecular data. RT-PCR of RNA from fixed paraffin-embedded ccRCC tissue was performed without knowledge of clinical data. Recurrence-free internval (RFI) was analyzed using Cox regression stratified by stage with data censored at 5 years, and Kaplan-Meier methods. Multivariable models incorporating the Leibovich score were used to assess the additional contribution of the RS to prediction of recurrence. Within- and between-tumor block reproducibility was assessed in an independent study using two separate tumor blocks from 8 pts, where each block was analyzed at 3 depths. Results: RS was generated in 626/645 pts (97%): 398 stage I, 54 stage II, 174 stage III. Median follow up was 5.5 yrs. The RS was significantly associated with risk of recurrence after adjustment for the Leibovich score (HR=4.20, p<0.001). Additionally, the performance of RS was similar across age groups (<60, 60-70 or ≥70), gender, nephrectomy type, tumor size (≤4, 4-7 or >7cm), grade, and presence/absence of invasion (all interaction p>0.29). Within-patient variability in the score (std. dev. of 1.73 and 4.74 RS units for within- and between-tumor block, respectively) was lower than patient-to-patient variability (std. dev. of 15.6 in validation study). Conclusions: The 16-gene signature remains strongly associated with risk of recurrence after adjustment for the Leibovich score and performs consistently across clinically relevant subgroups. Examination of within-patient and between-patient variability indicates that the score is robust to tumor heterogeneity.

scholarly journals Porcupine Inhibitor LGK974 Downregulates the Wnt Signaling Pathway and Inhibits Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Jianyi Li ◽  
Guangzhen Wu ◽  
Yingkun Xu ◽  
Jiatong Li ◽  
Ningke Ruan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Wnt Signaling ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Renal Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Wnt Signaling Pathway ◽  
Cell Renal Cell Carcinoma ◽  
Wnt Proteins

Targeted therapy for kidney cancer has achieved significant clinical results. However, because most patients who use targeted therapy will develop drug resistance, we still need to constantly explore new therapeutic targets. Although porcupine (PORCN) as a palmitoyltransferase plays a crucial role in the activation and secretion of Wnt proteins and affects the activity of the Wnt signaling pathway, little is known about the role of PORCN in clear cell renal cell carcinoma (ccRCC). We found that PORCN is highly expressed in renal cancer cell lines and patients with renal cell carcinoma with high expression of PORCN have a poor prognosis. Pathway analysis of PORCN and its related proteins showed that PORCN played a role through the Wnt signaling pathway, and there was a strong coexpression relationship between PORCN and Wnt proteins. Therefore, PORCN may be a potential and effective target for ccRCC. In the present study, we found that LGK974 could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We also found that LGK974 could inhibit the migration and invasion of renal cell carcinoma and reduce the expression of mesenchymal markers. After treatment with LGK974, the expression level of β-catenin, a key protein in the classical Wnt pathway, was significantly decreased, and the expression levels of the target genes cyclin D1, c-Myc, MMP9, and MMP2 in the Wnt signaling pathway were also significantly decreased, which represented a significant decrease in the activity of the Wnt signaling pathway. At the same time, the cycle of renal cancer cells was significantly blocked. In conclusion, our results indicate that LGK974 could significantly inhibit the progression of renal cancer cells in a safe concentration range, so PORCN may be a safe and effective target for patients with renal cancer.

scholarly journals mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

2020 ◽  
Author(s):  
Xuyang Zhao ◽  
Yadong Ma ◽  
Jie Cui ◽  
Haiyang Zhao ◽  
Lei Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Molecular Mechanism ◽  
Renal Cancer ◽  
Cancer Progression ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Invasion And Migration ◽  
And Migration

AbstractClear cell renal cell carcinoma (ccRCC), as the most important type of renal carcinoma, has a high incidence and easy metastasis. Folliculin (FLCN) was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of kidney cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion and migration in clear cell renal cell carcinoma remains elusive.In this study, we demonstrated that FLCN controled cell proliferation, invasion and migration through PI3K/mTORC2 pathway. FLCN combined with HIF2α in various normal and cancerous renal cells, and mTORC2 mediate FLCN effectively alleviated the deterioration of renal cancer cells by degrading HIF2α. Silencing of FLCN showed promotion of HIF2α protein expression, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, when interfering with siFLCN, HIF2α degradation rate was delayed, and the time of entry into the nucleus was advanced. Taken together, our study illustrated that mTORC2 promoted the specific molecular mechanism of HIF2α by down-regulated FLCN, and might be a new therapeutic target against renal cancer progression.

scholarly journals GATA3 suppresses human fibroblasts-induced metastasis of clear cell renal cell carcinoma via an anti-IL6/STAT3 mechanism

2019 ◽  
Vol 27 (9) ◽  
pp. 726-738 ◽  
Author(s):  
Qianqian Shi ◽  
Renfang Xu ◽  
Guanglai Song ◽  
Hao Lu ◽  
Dong Xue ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Conditioned Medium ◽  
Renal Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Normal Fibroblast ◽  
Cell Renal Cell Carcinoma ◽  
Renal Cancer Cell

AbstractTumorigenesis and metastasis depend on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. It is, however, unclear regarding the molecular mechanisms underlying the progress and metastasis of human clear-cell renal cell carcinoma in the microenvironment with fibroblasts. In this work, we investigated the effect of normal fibroblasts on the metastasis of renal cancer and the relevant signaling pathways. We isolated normal fibroblasts from normal renal tissues and used normal fibroblast-conditioned medium culture renal cancer cells. The CCK-8 and transwell assays showed that normal fibroblasts conditioned medium significantly enhanced ccRCC cell migration. IL6 mediated the cross talk between normal fibroblasts and the cancer cells, and promoted tumor cell migration through the STAT3 pathway. In contrast, GATA3 was downregulated at both mRNA and protein levels in the normal fibroblast-conditioned medium treated with renal cancer cells, but upregulated in adjacent normal tissues. GATA3 overexpression significantly reduced STAT3 phosphorylation and attenuated the migration in both renal cancer cell and IL6-stimulated renal cancer cell. Taken together, our findings suggest that the IL6/STAT3 pathway plays a crucial role in the normal fibroblast-enhanced clear-cell renal cell carcinoma metastasis, while GATA3 may mitigate this effect by inhibiting IL6/STAT3 signaling.

Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma

2007 ◽  
Vol 292 (2) ◽  
pp. F780-F788 ◽  
Author(s):  
Adolfo Varona ◽  
Lorena Blanco ◽  
José I. López ◽  
Javier Gil ◽  
Ekaitz Agirregoitia ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Aminopeptidase N ◽  
Aminopeptidase Activity ◽  
Peptidase Activity ◽  
Cell Renal Cell Carcinoma ◽  
Aspartyl Aminopeptidase

Peptides play important roles in cell regulation and signaling in many tissues and are regulated by peptidases, most of which are highly expressed in the kidney. Several peptide convertases have a function in different tumor stages, and some have been clearly characterized as diagnostic and prognostic markers for solid tumors, including renal cancer; however, little is known about their in vivo role in kidney tumors. The present study compares the activity of a range of peptidases in human tumor samples and nontumor tissue obtained from clear cell renal cell carcinoma (CCRCC) patients. To cover the complete spectrum and subcellular distribution of peptide-converting activity, acid, neutral, basic, and omega activities were selected. CCRCC displays a selective and restricted pattern of peptidase activities. Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopeptidase N decreases (t = 6,664 vs. n = 33,381 UP/mg protein; P < 0.001). Aminopeptidase B activity of the particulate fraction in tumors decreases (t = 2,399 vs. n = 13,536 UP/mg protein; P < 0.001) compared with nontumor tissues, and aspartyl-aminopeptidase activity decreases significantly in CCRCC (t = 137 vs. n = 223 UP/mg protein; P < 0.05). Soluble and particulate pyroglutamyl peptidase I activities, aminopeptidase A activity, and soluble aminopeptidase B activity do not vary in renal cancer. The relative expression for the aforementioned peptidases, assayed using quantitative RT-PCR, increases in CCRCC for aminopeptidases B (1.5-fold) and A (19-fold), aspartyl-aminopeptidase (3.9-fold), puromycin-sensitive aminopeptidase (2.5-fold), and pyroglutamyl peptidase I (7.6-fold). Only aminopeptidase N expression decreases in tumors (1.3-fold). This peptidase activity profile in the neoplastic kidney suggests a specific role for the studied convertases and the possible involvement of an intracrine renin-angiotensin system in the pathogenesis of CCRCC.

638: Macroscopic Tumor Necrosis is a Prognostic Indicator for Non-Metastatic Clear Cell Renal Cell Carcinoma

2007 ◽  
Vol 177 (4S) ◽  
pp. 214-214
Author(s):  
Sung Kyu Hong ◽  
Byung Kyu Han ◽  
In Ho Chang ◽  
June Hyun Han ◽  
Ji Hyung Yu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Necrosis ◽  
Clear Cell ◽  
Prognostic Indicator ◽  
Cell Renal Cell Carcinoma ◽  
Macroscopic Tumor

Rare localization of renal cell carcinoma metastases in the paranasal sinuses and breast: a case report

2019 ◽  
Vol 22 (6) ◽  
pp. 13-22
Author(s):  
E. V. Kryaneva ◽  
N. A. Rubtsova ◽  
A. V. Levshakova ◽  
A. I. Khalimon ◽  
A. V. Leontyev ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Paranasal Sinuses ◽  
Renal Cell ◽  
Clinical Case ◽  
Clear Cell ◽  
Malignant Tumors ◽  
Metastatic Potential ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Lesions

This article presents a clinical case demonsratinga high metastatic potential of clear cell renal cell carcinoma combined with atypical metastases to breast and paranasal sinuses. The prevalence of metastatic lesions to the breast and paranasal sinuses in various malignant tumors depending on their morphological forms is analyzed. The authors present an analysis of data published for the last 30 years. The optimal diagnostic algorithms to detect the progression of renal cell carcinoma and to evaluate the effectiveness of the treatment are considered.

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