Somatic von Hippel–Lindau disease gene mutation in clear‐cell renal carcinomas associated with end‐stage renal disease/acquired cystic disease of the kidney

Abstract

It has been documented that renal cell carcinomas (RCCs) occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). To address the molecular pathogenesis of ESRD/ACDK-associated RCCs, we examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) in patients receiving dialysis for somatic mutations of the von Hippel-Lindau disease (VHL) gene as well as of the tyrosine kinase domain of the MET oncogene. Direct sequencing analyses revealed that three tumors exhibited VHL frameshifts (618delA, 386-395del10-bp, and 723-724insTC). One of the VHL mutated tumors showed additional loss of heterozygosity at the VHL gene locus. Histopathologic and clinical data demonstrated that the three tumors having VHL mutations were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis history, respectively. We did not find any tumors with mutations in the tyrosine kinase domain of the MET. These results demonstrated that the VHL tumor-suppressor gene is also involved in a subset of clear-cell RCCs occurring in ESRD/ACDK, as in the case of sporadic clear-cell RCCs. However, mutations of the MET oncogene could not be found in the seven ESRD/ACDK-associated papillary RCCs examined.

Uncommon and recently described renal carcinomas

“…97 Genetic studies on carcinomas associated with end-stage kidneys are limited, however, clear cell carcinoma arising in these kidneys have shown VHL gene mutations. 98,99 Additional to recognized forms of renal neoplasia, two novel tumors associated with end-stage renal failure have been described. 96 One of these designated acquired cystic disease-associated renal cell carcinoma, was present in 46% of kidneys with acquired cystic disease.…”

“…98 Mutations of the VHL gene have not yet been identified in these tumors. 101 The second form of novel tumor associated with end-stage renal disease is papillary clear cell renal cell carcinoma (Figure 28).…”

Perspectives in drug development for metastatic renal cell cancer

“…HIF promotes transcription of CAIX; Glut1 glucose transporter enzymes for glucose metabolism and uptake; and numerous genes involved in angiogenesis such as VEGF, platelet-derived growth factor (PDGF), and transforming growth factor alpha (TGFα) [19]. Molecular profiling has also identified a frequent mutation (40-50%) or inactivation via promoter methylation (5-20%) within the tumor suppressor gene von Hippel-Lindau (VHL) in the majority of patients with sporadic ccRCC [20][21][22][23]. VHL is involved in the cellular response to hypoxia by targeting HIF-1α for ubiquitination and intracellular destruction via proteasomes [24].…”

Erworbene zystische Nierenerkrankung

“…In etwa 25-30% der Fälle finden sich intratumoral Ablagerungen von Kalziumoxalat, dies kommt nur bei Karzinomen mit hoher proximal-tubulärer Differenzierung vor [24]. Auch der genetische Hintergrund der Nierenzellkarzinome in Assoziation mit zystischer Nierendegeneration scheint unterschiedlich zu sein [22,25,26,27,28]. Man definiert von histopathologischer Seite die Entität des "acquired cystic disease-associated renal cell carcinoma", welches das häufigste bei Patienten mit terminaler Niereninsuffizienz ist (36%), meist eine papilläre Architektur aufweist mit Übergangsformen und häu-fig intratumorale Kalziumoxalatablagerungen zeigt [24,29].…”