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

Author(s):  
Anna Reustle ◽  
Steffen Rausch ◽  
Stefan Winter ◽  
Florian Büttner ◽  
Stephan Kruck ◽  
...  
2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Brian Shuch ◽  
Ryan Falbo ◽  
Fabio Parisi ◽  
Adebowale Adeniran ◽  
Yuval Kluger ◽  
...  

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.


2017 ◽  
Vol 471 (1) ◽  
pp. 107-115 ◽  
Author(s):  
Julien Dagher ◽  
Solène-Florence Kammerer-Jacquet ◽  
Frédéric Dugay ◽  
Marion Beaumont ◽  
Alexandra Lespagnol ◽  
...  

2013 ◽  
Vol 21 (3) ◽  
pp. 1046-1054 ◽  
Author(s):  
Joana Heinzelmann ◽  
André Unrein ◽  
Ulrike Wickmann ◽  
Sophie Baumgart ◽  
Marcus Stapf ◽  
...  

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 474-474 ◽  
Author(s):  
Maria Isabel Carlo ◽  
Nabeela Khan ◽  
Yingbei Chen ◽  
James Hsieh ◽  
A. Ari Hakimi ◽  
...  

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]


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4565-4565 ◽  
Author(s):  
Ritesh Kotecha ◽  
Erika Gedvilaite ◽  
Samuel J. Murray ◽  
Robert J. Motzer ◽  
Dana Tsui ◽  
...  

4565 Background: Circulating tumor DNA (ctDNA) assessment is a non-invasive approach for genomic interrogation of solid tumors. As a novel tool, key benchmarks for applications in metastatic clear cell renal cell carcinoma (mccRCC) are yet to be determined. To understand the utility of ctDNA, we performed a large cohort analysis using a comparative genomics approach integrating matched primary tissue and ctDNA genomic data. Methods: Pts with prior tumor mutational profiles generated via next generation sequencing (NGS) from nephrectomy or metastatic specimens underwent single-time point plasma collection. Targeted NGS sequencing with MSK-IMPACT was performed on tumor and ctDNA with subsequent bi-directional cross genotyping using Waltz 2.0. All pts had matched germline comparison from peripheral blood; clinical data was extracted from medical record. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of < 30% allele frequency to remove germline mutations. Results: 111 mccRCC pts, of whom available IMDC-risk was favorable (35%), intermediate (60%), and poor-risk (5%) were included for analysis. The median time between tissue and ctDNA collection was 23 months (R: 1-177), and 96% of patients had undergone nephrectomy prior to ctDNA collection. In primary tissue sequencing, 64/111 (58%) from nephrectomy and 42/111 (42%) from metastatic sites, 569 unique alterations were identified across the whole cohort, with a median of 4 mutations/pt (R:1-23). RCC-specific alterations included VHL (88%), PBRM1 (48%), SETD2 (34%), KDM5C (17%), TP53 (14%). Across the cohort, 176 alterations were identified in ctDNA. With cross genotyping, ctDNA alterations concordant with primary tumors were detected in 20% (22/111 pts, 28 unique alterations) using stringent criteria with a median of 1 mutation/pt (R:1-2). Using liberal criteria, concordance with primary tumors was 59% (66/111 pts, 142 unique alterations) with a median of 2 mutations/pt (R: 1-8). Conclusions: This large cohort study matching oncogenomics from tumor and ctDNA highlights complexities and challenges of applying liquid biopsy in biomarker development in mccRCC.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5906
Author(s):  
Kristyna Prochazkova ◽  
Nikola Ptakova ◽  
Reza Alaghehbandan ◽  
Sean R. Williamson ◽  
Tomáš Vaněček ◽  
...  

(1) Background: There are limited data concerning inter-tumoral and inter-metastatic heterogeneity in clear cell renal cell carcinoma (CCRCC). The aim of our study was to review published data and to examine mutation profile variability in primary and multiple pulmonary metastases (PMs) in our cohort of four patients with metastatic CCRCC. (2) Methods: Four patients were enrolled in this study. The clinical characteristics, types of surgeries, histopathologic results, immunohistochemical and genetic evaluations of corresponding primary tumor and PMs, and follow-up data were recorded. (3) Results: In our series, the most commonly mutated genes were those in the canonically dysregulated VHL pathway, which were detected in both primary tumors and corresponding metastasis. There were genetic profile differences between primary and metastatic tumors, as well as among particular metastases in one patient. (4) Conclusions: CCRCC shows heterogeneity between the primary tumor and its metastasis. Such mutational changes may be responsible for suboptimal treatment outcomes in targeted therapy settings.


Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1142
Author(s):  
Falk Gühne ◽  
Philipp Seifert ◽  
Bernhard Theis ◽  
Matthias Steinert ◽  
Martin Freesmeyer ◽  
...  

PET/CT with prostate-specific membrane antigen (PSMA)-targeted tracers has been used in the diagnosis and staging of patients with clear cell renal cell carcinoma (ccRCC). For ccRCC primary tumors, PET parameters were shown to predict histologic grade and features. The aim of this study was to correlate PSMA PET/CT with histopathological findings in patients with metastatic recurrence of ccRCC. Patients with ccRCC who underwent PSMA-targeted PET/CT and subsequent histopathological evaluation of suspicious lesions were included. Specimens underwent immunohistochemical marking. Lesion diameter, volume and tracer uptake were correlated with the extent and intensity of molecular PSMA expression and with clinical findings. Twelve PET-positive lesions of nine patients were evaluated. Eleven ccRCC metastases and one prostate carcinoma were detected histopathologically. Molecular PSMA expression was detected in all lesions, which intensity and distribution did not correlate with PET parameters. PSMA-targeted PET/CT is a feasible tool for the evaluation of patients with ccRCC but cannot reliably predict histologic features of metastases. PSMA may also be expressed in malignant lesions other than ccRCC, leading to incidental detection of these tumors.


2021 ◽  
Vol 11 ◽  
Author(s):  
Suhua Gao ◽  
Lei Yan ◽  
Hongtao Zhang ◽  
Xiaoguang Fan ◽  
Xiaojing Jiao ◽  
...  

Clear cell renal cell carcinoma (ccRCC) is one of the most frequent pathological subtypes of kidney cancer, accounting for ~70–75%, and the major cause of mortality is metastatic disease. The difference in gene expression profiles between primary ccRCC tumors and metastatic tumors has not been determined. Thus, we report integrated genomic and transcriptomic analysis for identifying differentially expressed genes (DEGs) between primary and metastatic ccRCC tumors to understand the molecular mechanisms underlying the development of metastases. The microarray datasets GSE105261 and GSE85258 were obtained from the Gene Expression Omnibus (GEO) database, and the R package limma was used for DEG analyses. In summary, the results described herein provide important molecular evidence that metastatic ccRCC tumors are different from primary tumors. Enrichment analysis indicated that the DEGs were mainly enriched in ECM–receptor interaction, platelet activation, protein digestion, absorption, focal adhesion, and the PI3K–Akt signaling pathway. Moreover, we found that DEGs associated with a higher level of tumor immune infiltrates and tumor mutation burden were more susceptible to poor prognosis of ccRCC. Specifically, our study indicates that seven core genes, namely the collagen family (COL1A2, COL1A1, COL6A3, and COL5A1), DCN, FBLN1, and POSTN, were significantly upregulated in metastatic tumors compared with those in primary tumors and, thus, potentially offer insight into novel therapeutic and early diagnostic biomarkers of ccRCC.


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