The genomic landscape of metastatic non-clear cell renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 474-474 ◽  
Author(s):  
Maria Isabel Carlo ◽  
Nabeela Khan ◽  
Yingbei Chen ◽  
James Hsieh ◽  
A. Ari Hakimi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mtor Inhibitors ◽  
Driver Gene ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Targeted Next Generation Sequencing ◽  
Metastatic Sites

474 Background: Non-clear cell renal cell carcinoma (nccRCC) encompasses about 20% of RCC cases and includes a number of subtypes that vary clinically and molecularly. Compared to ccRCC, these tumors have more limited sensitivity to conventional anti-VEGF agents and mTOR inhibitors, and there is clear need for better therapies. Analysis of genomic alterations in potentially targetable pathways may lead to novel therapeutic development strategies. Methods: We retrospectively analyzed tumors from 112 patients with metastatic nccRCC with targeted next-generation sequencing (NGS) across a panel of >340 cancer-relevant genes. Matched tumor and normal was used to facilitate somatic calling. We report on recurrent alterations observed for nccRCC variants. Results: Median age was 53 years (range 12-77), 67% were male; 47% presented with metastatic disease and 53% with localized disease that later metastasized. NGS was performed on tissue from primary tumors (57%) or metastatic sites (43%). Subtype classifications included unclassified (44%), papillary (21%), chromophobe (13%), translocation (12%), and other (9%). The most frequently altered genes by subtype are included in table. 36% of unclassified or papillary tumors had a mutation in a putative driver gene amenable to targeted therapies, including MET, NOTCH1, SMARCB1, TSC1, TSC2, PIK3CA, and FGFR3. 3 chromophobe tumors and 1 translocation tumor had a mutation in a potentially targetable pathway. Conclusions: The mutation profiles of metastatic nccRCC vary by papillary, chromophobe, and translocation subtype, with unclassified tumors most approximating papillary subtype. Unclassified and papillary subtypes harbor frequent mutations in potentially targetable pathways that merit further investigation. [Table: see text]

scholarly journals MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Brian Shuch ◽  
Ryan Falbo ◽  
Fabio Parisi ◽  
Adebowale Adeniran ◽  
Yuval Kluger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Distant Tissue ◽  
Significant Expression ◽  
Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

Abstract 1493: Specific miRNA signatures characterize different metastatic sites in clear cell renal cell carcinoma

2014 ◽  
Author(s):  
Joana Heinzelmann ◽  
Franzsika Stolzenbach ◽  
Robert Schneeweiss ◽  
Ulrike Wickmann ◽  
Sophie Baumgart ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Sites

Abstract 1693: Nicotinamide N-methyltransferase in clear cell renal cell carcinoma primary tumors and metastases

2016 ◽  
Author(s):  
Anna Reustle ◽  
Steffen Rausch ◽  
Stefan Winter ◽  
Florian Büttner ◽  
Stephan Kruck ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors

scholarly journals IMPA2 Downregulation Enhances mTORC1 Activity and Restrains Autophagy Initiation in Metastatic Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 9 (4) ◽  
pp. 956 ◽  
Author(s):  
Chia-Hao Kuei ◽  
Hui-Yu Lin ◽  
Hsun-Hua Lee ◽  
Che-Hsuan Lin ◽  
Jing-Quan Zheng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Cellular Migration ◽  
Cell Renal Cell Carcinoma ◽  
Gene Set

Although mTOR inhibitors have been approved as first-line therapy for treating metastatic clear cell renal cell carcinoma (ccRCC), the lack of useful markers reduces their therapeutic effectiveness. The objective of this study was to estimate if inositol monophosphatase 2 (IMPA2) downregulation refers to a favorable outcome in metastatic ccRCC receiving mTOR inhibitor treatment. Gene set enrichment analysis predicted a significant activation of mTORC1 in the metastatic ccRCC with IMPA2 downregulation. Transcriptional profiling of IMPA2 and mTORC1-related gene set revealed significantly inverse correlation in ccRCC tissues. Whereas the enforced expression of exogenous IMPA2 inhibited the phosphorylation of Akt/mTORC1, artificially silencing IMPA2 led to increased phosphorylation of Akt/mTORC1 in ccRCC cells. The pharmaceutical inhibition of mTORC1 activity by rapamycin reinforced autophagy initiation but suppressed the cellular migration and lung metastatic abilities of IMPA2-silenced ccRCC cells. In contrast, blocking autophagosome formation with 3-methyladenine rescued the mitigated metastatic potential in vitro and in vivo in IMPA2-overexpressing ccRCC cells. Our findings indicated that IMPA2 downregulation negatively activates mTORC1 activity and could be a biomarker for guiding the use of mTOR inhibitors or autophagy inducers to combat metastatic ccRCC in the clinic.

Clear cell renal cell carcinoma: a comparative study of histological and chromosomal characteristics between primary tumors and their corresponding metastases

2017 ◽  
Vol 471 (1) ◽  
pp. 107-115 ◽  
Author(s):  
Julien Dagher ◽  
Solène-Florence Kammerer-Jacquet ◽  
Frédéric Dugay ◽  
Marion Beaumont ◽  
Alexandra Lespagnol ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Comparative Study ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors

MicroRNAs with Prognostic Potential for Metastasis in Clear Cell Renal Cell Carcinoma: A Comparison of Primary Tumors and Distant Metastases

2013 ◽  
Vol 21 (3) ◽  
pp. 1046-1054 ◽  
Author(s):  
Joana Heinzelmann ◽  
André Unrein ◽  
Ulrike Wickmann ◽  
Sophie Baumgart ◽  
Marcus Stapf ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Distant Metastases ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors

Association of PD-1 and PD-L1 protein expression in matched primary and metastatic renal cell carcinoma tumors.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 418-418 ◽  
Author(s):  
Brian I. Rini ◽  
Jennifer Yearly ◽  
Hari Dhakal ◽  
Christopher Przybycin
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Linear Regression Analysis ◽  
Matched Pair ◽  
Primary Tumors ◽  
Metastatic Site ◽  
Metastatic Sites

418 Background: Therapy targeting programmed death (PD)-1 and PD-L1 proteins has activity in metastatic renal cell carcinoma (mRCC). Expression of these proteins on tumor and infiltrating immune cells is associated with a higher response to drugs inhibiting this pathway. However, these associations have been made based on primary tumor expression, while therapy is directed against metastatic deposits. Methods: Patients with mRCC and metastases (all clear cell; 3 with sarcomatoid changes) who had undergone resection of both the primary and at least one metastatic tumor were included. Samples were evaluated for PD-1 and PD-L1 expression by immunohistochemistry using anti-PD-1 clone NAT105 and Merck proprietary anti-PD-L1 clone 22C3. Stained sections were scored for PD-1 and PD-L1 using a semi-quantitative 0 to 5 scale (0 = negative, 1 = rare, 2 = low, 3 = moderate, 4= high, 5 = very high). PD-1 expression was limited to cells with lymphoid morphology, PD-L1 expression was evaluated for both tumor and non-tumor (inflammatory, endothelial) cells. Linear regression analysis was performed to assess significance of correlations. Results: Fifty matched primary and metastatic RCC tissue sets were analyzed with 48 evaluable matched pairs. PD-1 score greater than 3 (considered positive) was detected in 9 primary tumors (18%) and 9 metastatic sites (18%). PD-L1 score greater than 3 was detected in 9 primary tumors (18%) and 12 metastatic sites (24%). There was a correlation between PD-1 scores for primary and metastatic pairs (R2=0.194; p<0.002) and between PD-L1 scores for primary and metastatic pairs (R2=0.319; p<0.0001). There was an association between PD-1 score and PD-L1 score for primary tumors (R2=0.513; p<0.0001) and for metastatic sites (R2=0.449; p<0.0001). For PD-1 score, there were 10 pairs (21%) in which either the primary or metastatic site score was ≥3, but the matched pair was < 3. For PD-L1 score, there were 9 pairs (19%) in which either the primary or metastatic site score was ≥3, but the matched pair was < 3. Conclusions: The expression of PD1 and PD-L1 in primary clear cell RCC tumors is correlated with metastatic site expression, although there are a substantial percentage of tumors with discordance.

Phenotypic differences in tumor-associated macrophages between metastatic and primary sites of clear cell renal cell carcinoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 105-105
Author(s):  
Yuji Miura ◽  
Takanobu Motoshima ◽  
Nanako Wakigami ◽  
Natsuki Kusada ◽  
Toshikazu Okaneya ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
M2 Macrophages ◽  
Cell Renal Cell Carcinoma ◽  
Paired Samples ◽  
Metastatic Lesions ◽  
Metastatic Sites

105 Background: Tumor-associated macrophages (TAMs) are one of the key contributors to the tumor microenvironment and are phenotypically differentiated into M1 and M2 macrophages. M1 macrophages stimulate anti-tumor immune responses, whereas M2 macrophages promote immunosuppression and are associated with tumor progression in clear cell renal cell carcinoma (ccRCC). However, little information is available regarding the difference in TAM polarization between primary and metastatic lesions of ccRCC. Methods: We collected paired samples of primary and matched metastatic sites from the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for Iba1, which is a common pan-macrophage marker, and CD163 and CD204, which are considered to be M2 macrophage markers, was performed on all paired samples. Results: Thirty-three paired primary and metastatic samples were available for IHC assessment in this analysis. The most common metastatic sites were lung (N = 26, 78.8 %) and lymph node (N = 3, 9.1 %). The mean (± standard deviation) cell density of Iba1+ TAMs was higher in metastatic lesions than in primary lesions (756 ± 267 mm2 vs. 581 ± 155 mm2, P = 0.0012). By contrast, the ratio of CD163+ and CD204+ to Iba1+ TAMs was significantly lower in metastatic lesions than in primary lesions (0.76 ± 0.30 vs. 0.90 ± 0.24, P = 0.0067 and 0.39 ± 0.27 vs. 0.67 ± 0.29, P = 0.0001, respectively). The median overall survival of patients with high- vs. low-density Iba1+, CD163+, and CD204+ TAMs in metastatic lesions was 120 vs. 92 months (log-rank P = 0.67), 120 vs. 58 months (log-rank P = 0.056), and 120 vs. 92 months (log-rank P = 0.35), respectively. Conclusions: TAMs in the metastatic lesions of ccRCC polarized towards an M1-like phenotype, although the total number of TAMs was greater in metastatic compared with primary lesions. The cell density of Iba1+, CD163+, and CD204+ TAMs in metastatic sites was not associated with overall survival in patients with ccRCC.

scholarly journals Recent advances in the systemic management of non-clear cell renal cell carcinoma: a review article

2020 ◽  
Vol 7 (9) ◽  
pp. 1446
Author(s):  
Soumish Sengupta ◽  
Supriya Basu ◽  
Kadambari Ghosh
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mtor Inhibitors ◽  
Immunohistochemical Analysis ◽  
Cell Renal Cell Carcinoma ◽  
Drug Of Choice ◽  
Platinum Based Chemotherapy

Non-clear cell renal cell carcinoma (nccRCC) is not as common as clear cell renal cell carcinoma (ccRcc). But then it is not uncommon in regular urological practice. It usually carries a grave prognosis. Authors need to converse ourselves with National comprehensive cancer network (NCCN) categories for evidence and we need to converse as well with NCCN categories for preferences. ‘Preferred intervention’ is based on superior efficacy, safety and evidence and when appropriate, affordability. ‘Other recommended interventions’ are somewhat less efficacious, more toxic, or based on less mature data or significantly less affordable for similar outcomes. ‘Useful in certain circumstances’ are interventions that may be used for a selected patient population. Clinical trials for targeted agents are mainly directed at ccRCC because of its high prevalence. According to the NCCN panel, enrolment in clinical trials is the preferred strategy for nccRCC. Outcomes of patients with nccRCC have improved with the introduction of targeted therapy. Precise pathological diagnosis of the types of nccRCC by immunohistochemical analysis is mandatory. This enables specific treatments for individual nccRCC. Currently TKIs are the drug of choice (both first and second line) for metastatic papillary RCC. Both TKIs and mTOR inhibitors are effective against chromophobe RCC. Platinum based chemotherapy should be used for metastatic CDC. Further evidence is required for management of nccRCC. 

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