Combined <i>Vhlh</i> and <i>Pten</i> Mutation Causes Genital Tract Cystadenoma and Squamous Metaplasia

Frew, Ian J.; Minola, Andrea; Georgiev, Strahil; Hitz, Manuela; Moch, Holger; Richard, Stéphane; Vortmeyer, Alexander O.; Krek, Wilhelm

doi:10.1128/mcb.02132-07

Cited by 40 publications

(34 citation statements)

References 51 publications

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“…Although PTEN mutations are rare in ccRCC, allele deletions and reduction of PTEN protein expression occur in ∼25% of the tumors (16,17), indicating its potential role in a considerable subset of tumors. Interestingly, a recent study supports the hypothesis that a cooperative interaction between functional PTEN and VHL is necessary to successfully suppress the formation of epididymal cystadenomas, which frequently occurs in human VHL patients (18). Based on these data, it is conceivable that in many ccRCC, the clinical outcome is mainly dependent on the integrity of pathways normally controlled by VHL and PTEN.…”

supporting

confidence: 52%

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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supporting

confidence: 52%

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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“…In mice, combined deletion of the two tumor-suppressor genes, VHL and PTEN, caused benign genital tract tumors with regions of cyst adenoma that were histologically identical to lesions found in VHL patients. 24 pVHL and PTEN also cooperatively suppress kidney cyst formation. 5 Combined conditional inactivation of VHL and PTEN in the mouse kidney elicits cyst formation.…”

Section: Discussionmentioning

confidence: 99%

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

et al. 2011

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Multilocular cystic renal cell carcinoma is a rare renal cell carcinoma with an excellent prognosis. To clarify the relationship with typical clear cell renal cell carcinoma, we evaluated 15 cases of multilocular cystic renal cell carcinomas diagnosed according to the 2004 WHO classification. Von Hippel Lindau (VHL) gene mutations were determined by whole genome amplification and direct sequencing. Carbonic anhydrase 9 (CAIX), a hypoxiainducible factor (HIF) target, paired box gene 2 (PAX2), cyclin-dependent kinase inhibitor p27 and glycogen synthase kinase 3-b (GSK3b) were immunohistochemically evaluated as members of the VHL protein (pVHL)-and phosphatase and tensin homolog (PTEN)-controlled pathways. VHL mutations were identified in 3 of 12 (25%) tumors. Inactivated GSK3b, decreased PTEN expression and PAX2 positivity were observed in the vast majority of the multilocular cystic renal cell carcinomas. Strong nuclear staining of p27 was seen in 14 of 15 cases. Compared with multilocular cystic renal cell carcinomas, expression frequencies of PAX2, p-GSK3b, PTEN and CAIX were similar in a set of low-grade, early-stage clear cell renal cell carcinomas, whereas only 30% had strong p27 positivity. These results are consistent with the hypothesis that multilocular cystic renal cell carcinomas are related at the molecular level with clear cell renal cell carcinomas. Maintenance of a strong subcellular p27 expression in all multilocular cystic renal cell carcinomas analyzed may in part explain the excellent prognosis of these tumor patients.

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“…Both epithelial and peritubular progenitor cells can be the cancer cell-oforigin in mouse models of prostatic cancer, whereas peritubular cells have been implicated in the human. 6 In the Pten1Vhl double geneknockout mouse model of epididymal cystadenoma, an increase in epithelial basal cells suggested to Frew et al 15 that the neoplasm was generated by basal cell proliferation without differentiation. Figure 1 Macroscopic appearance of the human epididymis.…”

Section: Epididymal Cancer Progenitor Cellsmentioning

confidence: 99%

Why are epididymal tumours so rare?

Yeung¹,

Wang²,

Cooper³

2012

Asian J Androl

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Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro-proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general.

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Combined Vhlh and Pten Mutation Causes Genital Tract Cystadenoma and Squamous Metaplasia

Cited by 40 publications

References 51 publications

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

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

VHL mutations and dysregulation of pVHL- and PTEN-controlled pathways in multilocular cystic renal cell carcinoma

Why are epididymal tumours so rare?

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