Mutational State of von Hippel-Lindau and Adenomatous Polyposis Coli Genes in Renal Tumors

Abstract

Genetic alterations of the von Hippel-Lindau (VHL) tumor suppressor gene and the adenomatous polyposis coli (APC) gene in renal tumors were examined by PCR-SSCP analysis and direct sequencing. Tissues from 58 primary sporadic human renal cell tumors (49 clear-cell carcinomas, 6 non-clear-cell carcinomas and 3 oncocytomas) from Japanese patients were used in this study. Somatic VHL mutations were detected in 26 (53%) of the clear-cell carcinomas, although no mutations in this gene were observed in any non-clear-cell carcinomas or oncocytomas. The frequency of mutations did not correlate with histological grade, clinical stage or any of several other clinical factors examined. No differences in the frequency of VHL mutations or in the exons where mutations occurred within the gene were evident when we compared our results with those reported for American patients. However, frame-shifts were more common in our Japanese panel of tumors than in American cases, where single-point mutations appear to be more frequent. No APC gene mutation was detected in any of our samples. These results indicate that VHL gene mutations are related to the carcinogenesis of the clear-cell type of primary renal cell carcinomas, whereas alteration of the APC gene is not involved in the pathogenesis of this cancer.

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

“…The role of Wnt/b-catenin signaling in RCC, however, is not yet fully understood. APC gene mutations are not involved in RCC (Suzuki et al, 1997), and b-catenin mutations are rare events in these tumors (Bilim et al, 2000). Recently, the decreased expression of negative regulators of Wnt signaling, SFRP1 and DKK-3, has been found in RCC (Kurose et al, 2004;Dahl et al, 2007;Gumz et al, 2007).…”

The von Hippel–Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells

“…Initial investigations suggest that activating mutations in ␤-catenin are rare in RCC tumors (39)(40)(41), and no inactivating mutations in APC or axin have been reported in RCC (47,48). Oncogenic ␤-catenin signaling can also be initiated through aberrant Wnt stimulation or loss of negative repressors of Wnt signaling, such as members of the Dkk family.…”

Genetic analysis of von Hippel-Lindau disease

“…Somatic biallelic inactivating VHL mutations are involved in sporadic clear cell RCC tumorigenesis in up to 80% of samples [Bailly et al, 1995;Foster et al, 1994;Gallou, 1999Gallou, , 2001Gallou, , 2004Gnarra et al, 1994;Kanno et al, 1996;Prowse et al, 1997;Shuin et al, 1994;Suzuki et al, 1997;van Houwelingen et al, 2005]. Similarly, sporadic RCC in patients exposed to the industrial solvent trichloroethylene (TCE) display similar histopathological features and also harbor VHL mutations [Brauch, 2004;Brüning et al, 1997;Charbotel et al, 2007;Shiao, 2009;Wells et al, 2009].…”