Detection of a germline mutation and somatic homozygous loss of the von Hippel-Lindau tumor-suppressor gene in a family with a de novo mutation

Abstract

von Hippel-Lindau (VHL) disease is a pleiotropic disorder featuring a variety of malignant and benign tumors of the eye, central nervous system, kidney, and adrenal gland. Recently the VHL gene has been identified in the chromosomal region 3p25-26. Prognosis and successful management of VHL patients and their descendants depend on unambiguous diagnosis. Due to recurrent hemangioblastomas, a29-year-old patient without familial history of VHL disease was diagnosed to be at risk for the disease. Histopathological examination of a small renal mass identified a clear cell tumor with a G1 grading. Genetic characterization of the germline and of the renal tumor was performed. Polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL gene identified a deletion of a single nucleotide in exon 2 in the patient's germline and in the tumor, but not in the DNA of his parents. This deletion therefore must be a de novo mutation. Comparative genome hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of the G1 tumor with differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p and of the 3p26 signals, respectively. In conclusion, we identified a de novo germline mutation in the VHL gene of a young patient and a somatic chromosome 3p loss at the homologous chromosome 3 in his renal tumor. Our results suggest a recessive mode of inactivation of the VHL gene, providing solid evidence for its tumor-suppressor gene characteristics. Our data show the diagnostic potential of genetic testing, especially in patients without VHL family history. Furthermore, the findings of homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.

Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma

“…Frequent losses of chromosome 1, 2, 6, 10, 13, 17, and 21 and gains in chromosome 4, 7, 11, 12, 14q and 18q were observed in chRCC, consistent with previously reported data [18,19]. For renal oncocytoma, we show a high prevalence of chromosome 1p loss.…”

Human chromosome 7 carries a putative tumor suppressor gene(s) involved in choriocarcinoma

“…Because of the total loss of particular genetic information, the cellular eect of most homozygous deletions is assumed to be deleterious. Indeed, the homozygous deletions reported to date are relatively small and have been noted only in a few malignancies (Ohnishi et al, 1996;Kastury et al, 1996;Boyd et al, 1993;Schutte et al, 1995;Roche et al, 1996;Decker et al, 1996). The monoallelic contribution could contribute to the high incidence of homozygous deletions in choriocarcinomas.…”

Intramedullary Spinal Cord Tumors: Part I—Epidemiology, Pathophysiology, and Diagnosis

“… 90 Briefly summarized, mutation of a tumor suppressor gene located on chromosome 3p25–26 is responsible for this condition. 21 22 The VHL tumor suppressor proteins form a protein complex that interacts with elongins B and C and other proteins, marking them for degradation by the cell, which inhibits hypoxia-related cell transcription factors (HIF1a, HIF2a). 19 23 The VHL proteins also suppress the hypoxia-induced production of vascular endothelial growth factor, erythropoietin, and platelet-derived growth factor.…”