Analysis of the expression of Wnt signaling ligands in metastatic renal cell carcinomas tissue samples.

e15077 Background: Renal cell carcinomas (RCC) constitute a morphologically and genetically heterogeneous tumor.Wnt proteins are a large family of secreted glycoproteins that activate intracellular signal transduction pathways to control a wide variety of cellular processes such as determination of cell fate, proliferation, migration, and polarity.Wnt signalling may be playing a central role during RCC development. Methods: To characterize Wnt signalling activity in RCC, we gathered 48 tumor samples from patients diagnosed with metastatic RCC between years 2006 and 2011. Expression levels of Wnt family members (Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt7a, and Wnt9a) were examined by real-time PCR and immunohistochemistry in tumor and normal tissue from removed kidneys. Results: Wnt1 and Wnt5a were up-regulated in clear cell RCC being their relative expression 2.4.103 (Wnt1) and 4.102 (Wnt5a) times higher in renal tumor tissue than in normal tissue. One-way ANOVA test showed Wnt3a and Wnt4 as the best protein markers to distinguish clear cell RCC (F=3.95, p=0.010 and F=3.05, p=0.029, respectively). Wnt1 and Wnt7a were over-expressed in those cases which had undergone nefrectomy (Mann-Whitney U test p=0.065 and p=0.056 respectively). Finally, Wnt2 protein level was associated with those patients with high risk prognosis (Kruskal-Wallis test p=0.001). Conclusions: Our results indicate that Wnt3a and Wnt4 are potentially useful immunohistochemical markers for the differential diagnosis between clear cell RCC and other subtypes of RCC and also suggest a role for Wnt2 as a high risk prognosis marker.

Download Full-text

Exploring the miRNA-mRNA Regulatory Network in Clear Cell Renal Cell Carcinomas by Next-Generation Sequencing Expression Profiles

BioMed Research International ◽

10.1155/2014/948408 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 26

Author(s):

Sören Müller ◽

Katharina Nowak

Keyword(s):

Mirna Expression ◽

Renal Cell ◽

Messenger Rna ◽

Clear Cell ◽

Expression Profiles ◽

Independent Study ◽

Differentially Expressed ◽

Small Rna Sequencing ◽

Renal Cell Carcinomas ◽

Tissue Samples

Altered microRNA (miRNA) expression is a hallmark of many cancer types. The combined analysis of miRNA and messenger RNA (mRNA) expression profiles is crucial to identifying links between deregulated miRNAs and oncogenic pathways. Therefore, we investigated the small non-coding (snc) transcriptomes of nine clear cell renal cell carcinomas (ccRCCs) and adjacent normal tissues for alterations in miRNA expression using a publicly available small RNA-Sequencing (sRNA-Seq) raw-dataset. We constructed a network of deregulated miRNAs and a set of differentially expressed genes publicly available from an independent study toin silicodetermine miRNAs that contribute to clear cell renal cell carcinogenesis. From a total of 1,672 sncRNAs, 61 were differentially expressed across all ccRCC tissue samples. Several with known implications in ccRCC development, like the upregulated miR-21-5p, miR-142-5p, as well as the downregulated miR-106a-5p, miR-135a-5p, or miR-206. Additionally, novel promising candidates like miR-3065, whichi.a.targetsNRP2andFLT1, were detected in this study. Interaction network analysis revealed pivotal roles for miR-106a-5p, whose loss might contribute to the upregulation of 49 target mRNAs, miR-135a-5p (32 targets), miR-206 (28 targets), miR-363-3p (22 targets), and miR-216b (13 targets). Among these targets are the angiogenesis, metastasis, and motility promoting oncogenesc-MET,VEGFA,NRP2, andFLT1, the latter two coding for VEGFA receptors.

Download Full-text

Expression of Notch family members in stage IV renal cell carcinoma tumors: Notch1 as medium-risk prognosis factor.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15076 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15076-e15076

Author(s):

Luis M. Antón Aparicio ◽

Vanessa Medina Villaamil ◽

Guadalupe Aparicio Gallego ◽

Maria Quindós Varela ◽

Sergio Vazquez-Estevez ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Prognostic Markers ◽

Clear Cell ◽

Family Members ◽

Stage Iv ◽

Medium Risk ◽

Clear Cell Rcc ◽

Risk Prognosis

e15076 Background: The characterization of factors involved in the etiology of renal cell carcinoma (RCC) may lead to the identification of new targets for therapy and prognostic markers. Recent data indicate that Notch family members can be expressed by malignant RCC cells and this expression may have potential use as a strong prognostic factor. The aim of this study was to investigate the potential of Notch family members as prognostic markers for stage IV patients. Methods: We analyzed, by means of immunohistochemistry and quantitative polymerase chain reaction, protein and mRNA levels of 4 Notch family members in tumor specimens obtained from 48 patients with stage IV RCC. Clinicopathological data for these patients were evaluated. A 34% of the population had hypertension, 7.3% had hypothyroidism, 19.5% were diabetic, 7.7% prediabetic, and 22% showed hyperlipidemia. RCC specimens included clear cell RCC: 34; papillary: 3; mixed: 1; undifferentiated: 1; hypernephroma: 1.The association among biomarkers and clinicopathological factors were explored using One-Way ANOVA test and non-parametric statistics, Mann-Whitney U and Kruskal-Wallis tests. Results: Relative expression of Nocth3 and Notch4 transcript levels were elevated 25-fold in clear cell RCC tumors when compared with normal kidney tissues. Notch1 and Notch2 were overexpressed at protein level in clear cell RCC (p>0.05). Those renal tumors with right localization showed highest levels of Notch4 protein (p=0.096). Notch2 overexpression was associated with patients who had undergone nefrectomy (p=0.038). Finally, Bonferroni post-hoc statistic test showed us a statistically significant association (p = 0.020) between Nocth1 protein expression levels and patients with medium risk prognosis. Conclusions: These results show a deregulated expression of Notch receptors in RCC and suggest a role for this pathway in the progression of this tumoral pathology.

Download Full-text

Clinical Utility of Chromosome Genomic Array Testing for Unclassified and Advanced-Stage Renal Cell Carcinomas

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2018-0104-oa ◽

2018 ◽

Vol 143 (4) ◽

pp. 494-504 ◽

Cited By ~ 6

Author(s):

Nicole K. Andeen ◽

Xiaoyu Qu ◽

Tatjana Antic ◽

Scott S. Tykodi ◽

Min Fang ◽

...

Keyword(s):

Renal Cell ◽

Clinical Utility ◽

Clear Cell ◽

Renal Tumors ◽

Renal Cell Carcinomas ◽

Duct Carcinoma ◽

Clinical Scenarios ◽

Genomic Array ◽

Clear Cell Rcc ◽

Array Testing

Context.— Cytogenomic analysis provides a useful adjunct to traditional pathology in the categorization of renal cell carcinomas (RCCs), particularly in morphologically ambiguous cases, but it has disadvantages, including cost. Objective.— To define the clinical scenarios in which this technology has direct clinical applications. Design.— DNA was isolated from paraffin-embedded tissue from 40 selected cases of RCC. Chromosome genomic array testing was performed using the OncoScan. Results.— Of 23 cases of unclassified renal tumors, 19 (83%) were reclassified with incorporation of cytogenetic and histologic features, including 10 as clear cell RCC, 2 as collecting duct carcinoma, 2 as papillary RCC, and 1 as novel TFEB-amplified tumor lacking TFEB translocation. Of 5 tumors with “hybrid” oncocytic features, 3 were reclassified as an eosinophilic variant of chromophobe RCC and 1 as oncocytoma. Appropriate staging in 2 patients was determined by identifying distinct, nonshared cytogenetic profiles. Of 11 cases of metastatic clear cell RCC, 7 (63%) had cytogenetic features associated with a poor prognosis. Conclusions.— We identified 5 scenarios in which chromosome genomic array testing has direct clinical utility: (1) to investigate unclassified RCCs, (2) to understand tumors with “hybrid” features and “collision” tumors, (3) to determine appropriate staging in questions of bilateral tumors and/or metastases, (4) to identify chromosomal aberrations in metastatic clear cell RCCs associated with a worse prognosis, and (5) to identify new entities. This has practical value in our institution, where a molecular profile diagnostically separating morphologically difficult to classify clear cell, papillary, chromophobe, and unclassified RCC influences treatment recommendations and clinical trial eligibility.

Download Full-text

Various Histological Types of Renal Cell Carcinoma Associated With Hereditary Papillary Renal Cell Carcinoma (HPRCC): a Case Report

10.21203/rs.3.rs-736943/v1 ◽

2021 ◽

Author(s):

Sophie FERLICOT ◽

Pierre-Alexandre Just ◽

Eva Compérat ◽

Etienne Rouleau ◽

Frédérique Tissier ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Papillary Renal Cell Carcinoma ◽

Type I ◽

Renal Cell Carcinomas ◽

Genomic Study ◽

Papillary Rcc ◽

Clear Cell Rcc

Abstract Background: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome. Case presentation: We describe the case of a 51-year-old man with a germline MET mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed seven years after the initial diagnosis corresponding to a clear cell RCC metastasis. Using FISH, the metastatic tumor presented a trisomy of chromosomes 7 and 17. These genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome.Conclusions: The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.

Download Full-text

FLUORESCENT IN SITU HYBRIDIZATION AND IMMUNOHISTOCHEMISTRY FOR SUBTYPING “NON-CLASSIFIABLE” RENAL CELL CARCINOMAS

Knowledge International Journal ◽

10.35120/kij3104921i ◽

2019 ◽

Vol 31 (4) ◽

pp. 921-924

Author(s):

Atanas Ivanov ◽

Vili Stoyanova

Keyword(s):

In Situ Hybridization ◽

Genetic Analysis ◽

Renal Cell ◽

Clear Cell ◽

Renal Tumors ◽

Renal Cell Carcinomas ◽

Trisomy 7 ◽

Papillary Rcc ◽

Clear Cell Rcc

Renal tumors account for about 3% of the malignancies in adults. Clear cell subtype renal cell carcinoma (RCC) and papillary RCC are the most common renal tubular epithelial carcinomas and their differentiation is important because they have a different prognosis and are associated with different treatment protocols. In most cases, histological features allow accurate diagnosis of renal cell carcinomas. There are also overlapping morphological findings between certain kidney neoplasms that make their subtyping extremely difficult. Some of them display papillary architecture but also have a clear cell component and it is not clear whether they should be classified as clear cell RCC or papillary RCC. In our study we performed an immunohistochemical and genetic analysis of 24 cases of RCC classified as non-classifiable with mixed papillary and clear cell components treated at Clinic of Urology in University Hospital "St. George "-Plovdiv. The mean age of patients was 54.5 years, and gender distribution: 60% male and 40% female. Based on the results of immunohistochemistry and fluorescence in situ hybridization (FISH), patients were stratified in 2 groups. The first group included 16 of the cases where strong immunoreactivity was found for alfa-methyl coenzyme A racemase (AMACR), with cytokeratin 7 (CK7) being present in 15 of these. In all cases in this group, FISH proved trisomy 7 and 17, in 4-9p deletion, and in 2- 3p deletion. The remaining 8 cases were stratified in the second group - all negative for CK7 and only one positive for AMACR. Genetic analysis showed a lack of trisomy 7 and 17 in all cases, as well as a deletion of 3p and 9p in 7 of them. The combination of immunohistochemical and genetic analyzes allows with a high accuracy to differentiate cases of papillary RCC from those with clear cell RCC.

Download Full-text

Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽

10.3390/cancers13153807 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3807

Author(s):

Pierangela Sepe ◽

Arianna Ottini ◽

Chiara Carlotta Pircher ◽

Andrea Franza ◽

Melanie Claps ◽

...

Keyword(s):

Renal Cell ◽

Kinase Inhibitors ◽

Clear Cell ◽

Case Reports ◽

Treatment Options ◽

Single Agent ◽

Growth Factor Receptor ◽

Mtor Inhibitors ◽

Cell Renal Cell Carcinoma ◽

Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

Download Full-text

Two Cases of Sporadic Eosinophilic Solid and Cystic Renal Cell Carcinoma in Manitoba Population

International Journal of Surgical Pathology ◽

10.1177/1066896921993229 ◽

2021 ◽

pp. 106689692199322

Author(s):

Seyed Mohammad Mohaghegh Poor ◽

Shivani Mathur ◽

Karl Kassier ◽

Janetta Rossouw ◽

Robert Wightman ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Preoperative Imaging ◽

Renal Neoplasm ◽

Renal Masses ◽

Cystic Renal Cell Carcinoma ◽

Eosinophilic Cytoplasm ◽

Clear Cell Rcc

Two sporadic cases of eosinophilic solid and cystic renal cell carcinoma (ESC RCC), at our institution, are presented in this study to contribute to the growing literature on this novel renal neoplasm. The first patient was a 38-year-old female with two synchronous renal masses measuring 3.5 and 1.9 cm on preoperative imaging. The second patient was a 44-year-old female with an incidental renal mass measuring 4 cm. Both patients underwent uncomplicated radical nephrectomies. The 1.9 cm mass in the first patient was consistent with clear cell RCC. The dominant mass in the first patient and the tumor in the second patient had microscopic and macroscopic findings in keeping with ESC RCC including a tan appearance, abundant eosinophilic cytoplasm, and CK20+ and CK7− staining. Both patients had an uncomplicated course following surgery with no evidence of local recurrence or distant metastatic disease for 1 and 2 years for the first and second patient accordingly. These cases contribute to a growing body of literature regarding ESC RCC including, to our knowledge, the first reported case of synchronous ESC RCC and clear cell RCC. Further research about this novel renal neoplasm is needed.

Download Full-text

Neo-Fs Index: A Novel Immunohistochemical Biomarker Panel Predicts Survival and Response to Anti-Angiogenetic Agents in Clear Cell Renal Cell Carcinoma

Cancers ◽

10.3390/cancers13061199 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1199

Author(s):

Jisup Kim ◽

Jee-Young Park ◽

Su-Jin Shin ◽

Beom Jin Lim ◽

Heounjeong Go

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Plasmacytoid Dendritic Cell ◽

Cytolytic Activity ◽

Immune Gene ◽

Protein Markers ◽

Cell Renal Cell Carcinoma ◽

Frameshift Indels

Background: Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Here, to develop biomarkers that predict survival and response to AAA, we evaluated the immunohistochemical expression of proteins whose genes frequently harbor frameshift indels in 638 ccRCC patients and correlated the individual and integrated markers with prognosis and AAA response. The mutational landscape was evaluated using targeted next-generation sequencing in 12 patients concerning protein markers. Immune gene signatures were retrieved from TCGA RNA seq data. Results: Five proteins (APC, NOTCH1, ARID1A, EYS, and filamin A) were independent adverse prognosticators and were incorporated into the Neo-fs index. Better overall, disease-specific and recurrence-free survival were observed with high Neo-fs index in univariate and multivariate survival analyses. Better AAA responses were observed with a high Neo-fs index, which reflected increased MHC class I, CD8+ T cell, cytolytic activity, and plasmacytoid dendritic cell signatures and decreased type II-IFN response signatures, as well as greater single-nucleotide variant (SNV) and indel counts. Conclusions: Neo-fs index, reflecting antitumor immune signature and more SNVs. and indels, is a powerful predictor of survival and AAA response in ccRCC.

Download Full-text

Detection of a peritumoral pseudocapsule in patients with renal cell carcinoma undergoing robot-assisted partial nephrectomy using enhanced MDCT

Scientific Reports ◽

10.1038/s41598-021-81922-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Makoto Toguchi ◽

Toshio Takagi ◽

Yuko Ogawa ◽

Satoru Morita ◽

Kazuhiko Yoshida ◽

...

Keyword(s):

Computed Tomography ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Partial Nephrectomy ◽

Renal Cell ◽

Clear Cell ◽

Robot Assisted ◽

High Attenuation ◽

Papillary Rcc ◽

Clear Cell Rcc

AbstractTo investigate the detection of peritumoral pseudocapsule (PC) using multi-detector row computed tomography (MDCT) for tumors resected by robot-assisted laparoscopic partial nephrectomy (RAPN) for T1 renal cell carcinoma (RCC). Study participants included 206 patients with clinical T1 RCC who underwent RAPN between October 2017 and February 2018. Two radiologists who were blinded to the pathological findings evaluated the computed tomography (CT) images. Radiological diagnosis of a PC was defined by a combination of observations, including a low-attenuation rim between the tumor and renal cortex in the cortico-medullary phase and a high-attenuation rim at the edge of the tumor in the nephrogenic or excretory phase. A PC was detected on CT in 156/206 tumors (76%) and identified by pathology in 182/206 (88%) tumors including 153/166 (92%) clear cell RCC, 13/14 (93%) papillary RCC, and 7/16 (44%) chromophobe RCC. In the whole cohort, CT findings showed a sensitivity of 81.3% (148/182), specificity of 66.7% (16/24), and positive predictive value of 94.9% (148/156). When the data were stratified according to pathological subtypes, MDCT was observed to have a sensitivity of 86.9% (133/153) and specificity of 61.5% (8/13) in clear cell RCC, sensitivity of 38.5% (5/13) and specificity of 100% (1/1) in papillary RCC, and sensitivity of 44.4% (4/7) and specificity of 66.7% (6/9) in chromophobe RCC. A low or high-attenuation rim around the tumor in the cortico-medullary or nephrographic-to-excretory phase indicates a PC of RCC, though the accuracy is not satisfactory even with 64- or 320-detector MDCT.

Download Full-text