Targeted therapies and biological modifiers in urologic tumors: pathobiology and clinical implications

López-Beltrán, Antonio; Kirkali, Ziya; Liu, Cheng; Egevad, Lars; López, Joaquín Luis Reyes; Blanca, Ana; Montironi, Rodolfo

doi:10.1053/j.semdp.2008.07.006

Cited by 8 publications

(14 citation statements)

References 101 publications

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“…For the purpose of targeted therapy it is especially important to classify the different subtypes of RCC. The histological types arise from different cells of origin in the kidney, different constellations of genetic alterations [3], and expression or mutation in different oncogenic pathways. Therefore, different subtypes offer different molecular candidates for targeted therapy, such as Tyrosine Kinase Inhibitors, Sorafenib and Sunitinib, mTOR inhibitors, Everolimus and Temsirolimus, etc.…”

Section: Introductionmentioning

confidence: 99%

New miRNA Profiles Accurately Distinguish Renal Cell Carcinomas and Upper Tract Urothelial Carcinomas from the Normal Kidney

et al. 2014

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BackgroundUpper tract urothelial carcinomas (UT-UC) can invade the pelvicalyceal system making differential diagnosis of the various histologically distinct renal cell carcinoma (RCC) subtypes and UT-UC, difficult. Correct diagnosis is critical for determining appropriate surgery and post-surgical treatments. We aimed to identify microRNA (miRNA) signatures that can accurately distinguish the most prevalent RCC subtypes and UT-UC form the normal kidney.Methods and FindingsmiRNA profiling was performed on FFPE tissue sections from RCC and UT-UC and normal kidney and 434 miRNAs were significantly deregulated in cancerous vs. the normal tissue. Hierarchical clustering distinguished UT-UCs from RCCs and classified the various RCC subtypes among them. qRT-PCR validated the deregulated expression profile for the majority of the miRNAs and ROC analysis revealed their capability to discriminate between tumour and normal kidney. An independent cohort of freshly frozen RCC and UT-UC samples was used to validate the deregulated miRNAs with the best discriminatory ability (AUC>0.8, p<0.001). Many of them were located within cytogenetic regions that were previously reported to be significantly aberrated. miRNA targets were predicted using the miRWalk algorithm and ingenuity pathway analysis identified the canonical pathways and curated networks of the deregulated miRNAs. Using the miRWalk algorithm, we further identified the top anti-correlated mRNA/miRNA pairs, between the deregulated miRNAs from our study and the top co-deregulated mRNAs among 5 independent ccRCC GEO datasets. The AB8/13 undifferentiated podocyte cells were used for functional assays using luciferase reporter constructs and the developmental transcription factor TFCP2L1 was proved to be a true target of miR-489, which was the second most upregulated miRNA in ccRCC.ConclusionsWe identified novel miRNAs specific for each RCC subtype and UT-UC, we investigated their putative targets, the networks and pathways in which they participate and we functionally verified the true targets of the top deregulated miRNAs.

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Section: Introductionmentioning

confidence: 99%

New miRNA Profiles Accurately Distinguish Renal Cell Carcinomas and Upper Tract Urothelial Carcinomas from the Normal Kidney

et al. 2014

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“…8 -11 The histological types arise through different constellations of genetic alterations and show expression or mutation in different oncogenic pathways; they therefore offer different molecular candidates for targeted therapy (eg, mTOR, VEGF, KIT). 14 -16 Initial studies show differences in the responses of RCC subtypes to targeted therapies, 16,17 and future therapies are likely to be individualized for the different types. 15 The correct identification of these subtypes is therefore important for choice of treatment and for the selection of patients for clinical trials.…”

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confidence: 99%

“…15 The correct identification of these subtypes is therefore important for choice of treatment and for the selection of patients for clinical trials. 16,18 Conventional RCC is the most frequent subtype of RCC and accounts for 60 to 70% of cases, thus causing the majority of renal cell cancer specific mortality. The term "conventional" is used to replace the name "clear cell," because some types have eosinophilic cytoplasm, generating a more difficult diagnostic challenge.…”

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confidence: 99%

Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Fridman

Dotan

Barshack

et al. 2010

The Journal of Molecular Diagnostics

103

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Subtypes of renal tumors have different genetic backgrounds, prognoses, and responses to surgical and medical treatment, and their differential diagnosis is a frequent challenge for pathologists. New biomarkers can help improve the diagnosis and hence the management of renal cancer patients. We extracted RNA from 71 formalin-fixed paraffin-embedded (FFPE) renal tumor samples and measured expression of more than 900 microRNAs using custom microarrays. Clustering revealed similarity in microRNA expression between oncocytoma and chromophobe subtypes as well as between conventional (clear-cell) and papillary tumors. By basing a classification algorithm on this structure, we followed inherent biological correlations and could achieve accurate classification using few microRNAs markers. We defined a two-step decision-tree classifier that uses expression levels of six microRNAs: the first step uses expression levels of hsa-miR-210 and hsa-miR-221 to distinguish between the two pairs of subtypes; the second step uses either hsa-miR-200c with hsa-miR-139-5p to identify oncocytoma from chromophobe, or hsa-miR-31 with hsa-miR-126 to identify conventional from papillary tumors. The classifier was tested on an independent set of FFPE tumor samples from 54 additional patients, and identified correctly 93% of the cases. Validation on qRT-PCR platform demonstrated high correlation with microarray results and accurate classification. MicroRNA expression profiling is a very effective molecular bioassay for classification of renal tumors and can offer a quantitative standardized complement to current methods of tumor classification.

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“…Defects in VHL expression result in constitutive activation of the hypoxia-inducible factor (HIF) pathway and overexpression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other products. Inactivation of the VHL gene also enhances tumor cell growth though the mammalian target of rapamycin (mTOR) pathway [8,10-12]. In contrast, papillary renal cell carcinoma (PRCC) is the most common non-clear cell subtype of RCC, accounting for 10%-15% of tumors.…”

Section: Introductionmentioning

confidence: 99%

Molecular subtyping of metastatic renal cell carcinoma: implications for targeted therapy

et al. 2014

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BackgroundRenal cell carcinoma (RCC) is known for its ability to metastasize synchronously or metachronously to various anatomic sites. Distinguishing histologic subtypes of metastatic RCC has become increasingly important, as prognosis and therapy can differ dramatically between subtypes. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping metastatic RCC in light of these potential therapeutic implications.ResultsSpecimens from 103 cases of metastatic RCC were retrieved, including 32 cases originally diagnosed as metastatic clear cell renal cell carcinoma (CCRCC), 8 as metastatic papillary renal cell carcinoma (PRCC), and 63 metastatic RCC without a specific subtype. Immunohistochemistry was performed with antibodies against cytokeratin 7 (CK7) and alpha-methylacyl-CoA racemase (AMACR). Dual color interphase fluorescence in situ hybridization was utilized to assess for deletion of chromosome 3p and trisomy of chromosomes 7 and 17 in all tumors. Chromosome 3p deletion was detected in 41% of all metastatic RCC specimens, and trisomy of chromosomes 7 and/or 17 was detected in 16%. Of metastatic CCRCC, chromosome 3p deletion was detected in 63%. Of metastatic PRCC, 75% showed trisomy of chromosomes 7 and/or 17. Of the tumors not previously classified, 6% were positive for CK7, and 64% were positive for AMACR; 35% showed chromosome 3p deletion, and 16% showed trisomy of chromosomes 7 and/or 17. Combined analysis of immunohistochemistry and cytogenetics enabled reclassification of 52% of these metastatic tumors not previously classified.ConclusionOur findings support the utility of immunohistochemistry and cytogenetics for subtyping metastatic RCC.

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Targeted therapies and biological modifiers in urologic tumors: pathobiology and clinical implications

Cited by 8 publications

References 101 publications

New miRNA Profiles Accurately Distinguish Renal Cell Carcinomas and Upper Tract Urothelial Carcinomas from the Normal Kidney

New miRNA Profiles Accurately Distinguish Renal Cell Carcinomas and Upper Tract Urothelial Carcinomas from the Normal Kidney

Accurate Molecular Classification of Renal Tumors Using MicroRNA Expression

Molecular subtyping of metastatic renal cell carcinoma: implications for targeted therapy

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