Prevalence, Morphology and Biology of Renal Cell Carcinoma in Von Hippel-Lindau Disease Compared to Sporadic Renal Cell Carcinoma

Neumann, Hartmut P. H.; Bender, Bernhard U.; Berger, Dietmar; Laubenberger, Jörg; Schultze-Seemann, Wolfgang; Wetterauer, Ulrich; FERSTL, JOSEF; Herbst, E. W.; Schwarzkopf, Georg; Hes, Frederik J.; Lips, Cornelis J.M.; Lamiell, James M.; Masek, O; Riegler, Peter; Mueller, Barbara M.; Glavač, Damjan; Brauch, Hiltrud

doi:10.1097/00005392-199810000-00011

Cited by 44 publications

(52 citation statements)

References 26 publications

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“…26 Interestingly, 5 of 20 (25%) of our ccRCCs displayed detectable phospho-serine 9-GSK3b (data not shown). Therefore, our findings suggest that cilia degeneration driven by VHL dysfunction and GSK3b inactivation is also an important mechanism of renal carcinogenesis in a significant fraction of non-VHL patients.…”

Section: Discussionmentioning

confidence: 78%

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

et al. 2009

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Renal cysts and clear cell renal cell carcinoma are common clinical manifestations of people with germ-line mutations of the von Hippel-Lindau tumor suppressor gene, VHL. Recent cell biological evidence suggests that the VHL gene product, pVHL, functions to maintain the primary cilium, a microtubule-based antenna-like structure whose functional integrity is believed to have an important role in cell-cycle control. As VHL mutations are common in sporadic clear cell renal cell carcinoma, but not papillary renal cell carcinoma, we asked whether there is an association between VHL status and primary cilia in vivo. VHL status was assessed in 20 cases of clear cell renal cell carcinoma and 9 cases of papillary renal cell carcinoma by DNA sequencing and by immunohistochemical staining for the hypoxia-inducible factor-a target gene products CA9 and GLUT-1. Of 20, 18 clear cell renal cell carcinomas, but only 1 of 9 papillary renal cell carcinomas, displayed evidence of VHL inactivation. In clear cell renal cell carcinoma the frequency of ciliated tumor cells ranged from 0 to 22% (median value 7.8±6.0%), whereas cilia frequency was significantly higher (Po0.0001) in papillary renal cell carcinoma (range 12-83%, median value 43.3 ± 21.3%). There was no correlation between Ki-67 staining and cilia frequency, suggesting that the observed differences between the tumor types in cilia frequency are not accounted for by differences in cellular proliferation rates and that primary cilia degeneration in sporadic clear cell renal cell carcinoma depends on VHL inactivation. We propose that the different ciliation status of clear cell and papillary renal cell carcinoma may contribute, at least in part, to the different biological behaviors of these tumor types.

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Section: Discussionmentioning

confidence: 78%

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

et al. 2009

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“…In humans with kidney malformations, PAX2 is highly expressed in cystic and hyperproliferative epithelial cells (45). Cysts also occur frequently in hereditary and sporadic ccRCC, which are thought to be a result of uncontrolled cell proliferation and represent tumor precursor lesions (46). The ability to transcriptionally repress the tumor suppressor p53 (47) and its joint action with CCND1 and mTOR makes PAX2 a possibly important promoter of cyst formation in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

Mining Tissue Microarray Data to Uncover Combinations of Biomarker Expression Patterns that Improve Intermediate Staging and Grading of Clear Cell Renal Cell Cancer

Dahinden

Ingold

Wild

et al. 2010

Clinical Cancer Research

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Purpose: Tumor stage and nuclear grade are the most important prognostic parameters of clear cell renal cell carcinoma (ccRCC). The progression risk of ccRCC remains difficult to predict particularly for tumors with organ-confined stage and intermediate differentiation grade. Elucidating molecular pathways deregulated in ccRCC may point to novel prognostic parameters that facilitate planning of therapeutic approaches.Experimental Design: Using tissue microarrays, expression patterns of 15 different proteins were evaluated in over 800 ccRCC patients to analyze pathways reported to be physiologically controlled by the tumor suppressors von Hippel-Lindau protein and phosphatase and tensin homologue (PTEN). Tumor staging and grading were improved by performing variable selection using Cox regression and a recursive bootstrap elimination scheme.Results: Patients with pT2 and pT3 tumors that were p27 and CAIX positive had a better outcome than those with all remaining marker combinations. A prolonged survival among patients with intermediate grade (grade 2) correlated with both nuclear p27 and cytoplasmic PTEN expression, as well as with inactive, nonphosphorylated ribosomal protein S6. By applying graphical log-linear modeling for over 700 ccRCC for which the molecular parameters were available, only a weak conditional dependence existed between the expression of p27, PTEN, CAIX, and p-S6, suggesting that the dysregulation of several independent pathways are crucial for tumor progression.Conclusions: The use of recursive bootstrap elimination, as well as graphical log-linear modeling for comprehensive tissue microarray (TMA) data analysis allows the unraveling of complex molecular contexts and may improve predictive evaluations for patients with advanced renal cancer. Clin Cancer Res; 16(1); 88-98. ©2010 AACR.The last decades have shown an incidental increase of patients diagnosed with renal cell carcinoma (RCC) with clear cell RCC (ccRCC) being the most frequent and aggressive subtype (1, 2). Patients with local tumors have a significantly better outcome as these cancers can be treated with radical or partial nephrectomy, whereas the 5-year survival rate of metastatic ccRCC remains poor. However, even in patients with organ-confined ccRCC, the 10-year cancer-specific death rates vary from 10% to 38% in pT1a and pT2 tumors, respectively (3).To date, the best available predictor of the postoperative clinical course of localized RCCs is tumor stage at presentation (4, 5). Nevertheless, a significant difference of outcome exists within the same stage. Additional prognostic parameters are routinely used to refine prognosis in RCC patients. After tumor stage, the second most important prognostic parameter is the nuclear differentiation grade (6). Three-and four-tired grading systems are commonly applied for tumor grading. More than 50% of ccRCCs are classified as moderately differentiated, implying an intermediate risk of tumor recurrence (7), which is not informative for the clinician to stratify therapy. Therefo...

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“…[179][180][181][182][183] Single cases of unilateral, unifocal RCC diagnosed at or after age 50 are insufficient to warrant referral to genetic counseling. 175,184 Referral should be considered for any individual with a personal history of or first-degree relative with (i) clear cell RCC if he or she (a) has bilateral or multifocal tumors, (b) is diagnosed before age 50, or (c) has a close relative with clear cell RCC; (ii) central nervous system hemangioblastoma; (iii) pheochromocytoma; (iv) endolymphatic sac tumor, or (v) retinal capillary hemangioma.…”

Section: Von Hippel-lindau Syndrome (Omim 193300)mentioning

confidence: 99%

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Hampel

Bennett

Buchanan

et al. 2015

Genetics in Medicine

468

326

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Cancer genetic consultation services include the evaluation of patients' personal and family history for concerning features of hereditary cancer predisposition syndromes, development of a differential diagnosis for one or more possible hereditary cancer syndromes, genetic testing if indicated and available, recommendations for management, cancer surveillance and prevention, and information regarding genetic counseling and genetic testing for at-risk relatives. This counseling is informed by the genetic Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peerreviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their firstdegree relatives meet any of these referral criteria.

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Prevalence, Morphology and Biology of Renal Cell Carcinoma in Von Hippel-Lindau Disease Compared to Sporadic Renal Cell Carcinoma

Abstract: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.

Cited by 44 publications

References 26 publications

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia

Mining Tissue Microarray Data to Uncover Combinations of Biomarker Expression Patterns that Improve Intermediate Staging and Grading of Clear Cell Renal Cell Cancer

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

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