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Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes.

ABSTRACT: PURPOSE:To evaluate prevalence and clinical impact of VHL mutations and deletions (3p), a cohort of consecutive kidney tumors was analyzed by DNA sequencing and fluorescence in-situ hybridization (FISH). PATIENTS AND METHODS:The study includes 1,805 patients with renal tumors who were surgically treated at the Department of Urology at the University Medical Center Hamburg-Eppendorf between 1994 and 2015. The cohort included 1,176 clear cell, 270 papillary, 101 chromophobe, and 28 clear cell (tubulo) papillary cancers, as well as 149 oncocytomas and 81 less common subtypes. RESULTS:Among 431 successfully analyzed tumors, VHL mutations were found in 59.3% of clear cell, 5.2% of papillary, 3.1% of chromophobe carcinomas and in 7.3% of oncocytomas as well as in the rare kidney tumor types (25%-60%). FISH analysis was successful in 1,403 cases. 3p25 deletion was found in 57.2% of clear cell, 17.6% of papillary, 17.7% of chromophobe carcinomas and in 11.9% of oncocytomas as well as in the rare kidney tumor types (16.7%-50%). No statistically significant associations between VHL mutation/deletion and tumor grade, stage, and clinical outcome was found. Only in the subgroup of papillary cancers, 3p deletion was significantly associated with lymph node and distant metastasis as well as with poor patient outcome (p < 0.05 each). CONCLUSIONS:The presence of a VHL mutation in virtually all renal tumor subtypes suggests that VHL analysis cannot be used to distinguish between renal tumor subtypes. Consequently, anti-VHL treatment strategies should not be limited to patients with clear cell cancer.

SUBMITTER: Buscheck F

PROVIDER: S-EPMC6980626 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes.

Büscheck Franziska F Fraune Christoph C Simon Ronald R Kluth Martina M Hube-Magg Claudia C Möller-Koop Christina C Sarper Imren I Ketterer Kathrin K Henke Tjark T Eichelberg Christian C Dahlem Roland R Wilczak Waldemar W Sauter Guido G Fisch Margit M Eichenauer Till T Rink Michael M

Oncotarget 20200121 3

<h4>Purpose</h4>To evaluate prevalence and clinical impact of VHL mutations and deletions (3p), a cohort of consecutive kidney tumors was analyzed by DNA sequencing and fluorescence <i>in-situ</i> hybridization (FISH).<h4>Patients and methods</h4>The study includes 1,805 patients with renal tumors who were surgically treated at the Department of Urology at the University Medical Center Hamburg-Eppendorf between 1994 and 2015. The cohort included 1,176 clear cell, 270 papillary, 101 chromophobe, ...[more]

PMID: 32076485

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Project description:Renal cancer accounts for 2% to 3% of all adult malignancies in the US. In 2011 more than 64,770 new cases and 13,000 deaths were reported and the incidence is steadily increasing by 2.5% per year. Clear cell renal carcinoma (ccRCC) represents the majority (85% to 90%) of adult kidney cancers and is the most malignant. This cancer is characterized by an early loss of the von Hippel-Lindau tumor suppressor (VHL) on short arm of chromosome 3 in the majority of tumors (80%). It is a classic knowledge that loss of VHL results in an increased accumulation and activity of the hypoxia-inducible transcription factor (HIF), which in turns activates expression of genes promoting tumor growth. In that respect, induction of angiogenic factors induces blood flow through the tumors and delivery of nutrients and oxygen to cancer cells, while induction of genes inducing anaerobic glycolysis supports adaptation to reduced nutrients availability and shifts towards metabolic pathways promoting tumor growth. Recently we have discovered another tumor suppressing pathway regulated by VHL. We found that VHL is a major regulator of the process of macroautophagy (autophagy) (ref). We identified that VHL induces expression of a microRNA, miR-204, which in turn inhibits activity of a major regulator required for the formation of autophagosome, LC3B. LC3B-mediated autophagy is necessary for the ccRCC tumor growth, and inhibition of this process by VHL and miR-204 significantly contributes to the tumor suppression. Most importantly, we discovered that VHL by inhibiting activity of HIF, induced expression and activity of an LC3B paralog, LC3C. In contrast to LC3B, LC3C acts as a tumor suppressor, indicating the specificity and complexity of different autophagic programs. Integrating these novel data with the established role of VHL in regulating angiogenesis produces a more global picture of VHL as a master tumor suppressor that regulates nutrient access for renal cancer cells from both extracellular and intracellular sources. In the process of searching for other genes induced by VHL that could participate in the tumor suppressing activity of VHL, we discovered that reconstitution of VHL in RCC cells induces enrichment of genes expressed from the Smith-Magenis locus (SM), located on the short arm of chromosome 17p11.2. Smith-Magenis syndrome is a complex neurobehevioural disorder, characterized by intellectual impairment, craniofacial and skeletal anomalies and sleep disturbance. Recently, deletions or mutations of one specific gene in the SM locus, RAI1, (retinoic acid induced 1), were shown to be responsible for the syndrome. Interestingly, this locus contains another kidney tumor suppressor gene, folliculin (FLCN), of which activity is lost in the genetic dominant disorder, Birt-Hogg-Dube syndrome (BHD). BHD is characterized by skin fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, as well as renal cancer of mixed histological types, including chromophobe, oncocytic, clear cell and papillary type. Here we show that VHL regulates expression of FLCN, and in turn FLCN contributes to the VHL-mediated suppression of tumor growth. Two-condition experiment, VHL(-) vs. VHL(+). 4 biological replicates in each group. Two dual-channel arrays with VHL(+) on Cy5 and VHL(-) on Cy3, and two dual-channel arrays with flipped samples.

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Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes.

Publications

Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes.

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