Renal Cell Carcinoma

Curti, Brendan D.

doi:10.1001/jama.292.1.97

Cited by 130 publications

(99 citation statements)

References 21 publications

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“…1,2 Approximately 25-30% of CC-RCC patients have metastatic disease at diagnosis, and 20-30% of patients with clinically localized CC-RCC develop metastasis post-nephrectomy. 3 Recent advances in the use of antiangiogenesis-targeted agents appear to have revolutionized treatment. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade.…”

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confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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confidence: 99%

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…The most common RCC subtypes are: clear cell (75%); papillary (15%); cromophobic (5%) and collecting duct carcinoma (2%) (2). Sarcomatoid degeneration may occur in any of the four RCC subtypes (1) and increases the risk related to the aggressiveness of the disease.…”

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confidence: 99%

Prognostic relevance of the histological subtype of renal cell carcinoma

et al. 2008

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Objective: According to several studies, when the histological subtype of renal cell carcinoma is established it is possible to attribute a different life expectancy to each patient. We analyzed the prognostic significance of the histological subtype in renal cell carcinoma. Materials and Methods:The authors retrospectively analyzed the follow-up of 230 patients after radical or conservative renal surgery. The histological characteristics of the different subtypes of tumor were obtained and the disease-free and cancer-specific survival curves for the clear cell, cromophobic, papillary, collecting duct (Bellini) subtypes and those with sarcomatoid differentiation were individualized. Results: The disease-free and cancer-specific survival rates for clear cell tumors were 76.6% and 68.0% respectively, 71.2% and 82.1% respectively for the cromophobic type, 71.1% and 79.8% respectively for the papillary type, 26.9% and 39.3% respectively for the sarcomatoid type, and 0.0% and 0.0% respectively for the collecting ducts (p < 0.001). Conclusion:The histological subtypes of renal tumors can stratify patients into different prognostic groups only when the sarcomatoid differentiation is present.

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“…1,2 RCC can display a highly variable biological and clinical behavior and available prognostic indicators (i.e., tumor stage and grade) are unable to accurately predict patient outcome, especially in clear cell RCC. 4,5 Disturbances in the interactions of cells with the extracellular matrix (ECM) play an important role in the development and progression of many types of cancer and an altered relationship between ECM and tumor cells is considered a hallmark of malignant transformation. 6 Dystroglycan (DG) is a major non-integrin adhesion molecule expressed in skeletal muscle and in a wide variety of tissues at the interface between the basement membrane and the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma

Sgambato

Camerini

Amoroso³

et al. 2007

Cancer Biology & Therapy

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The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor aggressiveness. In this study expression of the DG subunit was evaluated by immunostaining in a series of renal epithelial cancers and its relation with traditional prognostic indicators and with the clinical outcome of the patients was evaluated.aDG expression was undetectable in a significant fraction of tumors (54%). In renal cell carcinomas (RCC) loss of a-DG staining correlated with higher tumor grade (p = 0.02) but not with tumor stage nor tumor size. In clear cell RCC patients loss of aDG staining correlated with an increased risk of recurrence (p = 0.002 by log-rank test) and death (p = 0.004) also when patients with lower grade or stage tumors were analyzed separately. In a multivariate analysis loss of DG staining confirmed to be and independent predictor of shorter disease-free (p = 0.001; RR = 4.9) and overall (p = 0.009; RR = 4.9) survival stronger than tumor grade and size.These findings demonstrate that loss of aDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC.

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Renal Cell Carcinoma

Cited by 130 publications

References 21 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Prognostic relevance of the histological subtype of renal cell carcinoma

Expression of dystroglycan correlates with tumor grade and predicts survival in renal cell carcinoma

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