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B Zbar

Publications and source records attributed to B Zbar.

At least 73 records · Page 4Linked to original sources
PubMed1996

Chromosome imbalances in papillary renal cell carcinoma and first cytogenetic data of familial cases analyzed by comparative genomic hybridization.

We used comparative genomic hybridization to analyze 17 tumor samples from 11 patients with papillary renal cell carcinoma (RCC), including three patients with hereditary papillary RCC. Whereas the most frequent aberrations confirmed data obtained by banding analyses, copy number increases on 5q, which previously were considered characteristic of nonpapillary RCC, were identified in two cases. In two complex cases belonging to the same family, a characteristic pattern of chromosomal aberrations was found: five of the six imbalances present in the less complex case were included in the karyotype of the other case, suggesting a genetically determined mechanism resulting in genomic instability of specific chromosomes or chromosomal subregions and/or selection of specific mutations.

Adult↗
PubMed1996

Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene.

We report a three generation, 25 member kindred with familial pheochromocytoma. Seven subjects of generations I and II had pheochromocytoma, in five of the seven, the tumors were bilateral, and in two of the seven, the tumors were both adrenal and extraadrenal. One patient also had a carotid body chemodectoma, and one patient had a malignant adrenal tumor and abdominal paraganglioma. In the patient with the chemodectoma, a cerebellar hemangioblastoma became manifest 25 yr after his initial diagnosis with pheochromocytoma, leading only then to a clinical diagnosis of von Hippel-Lindau disease (VHL). A mutational analysis of the VHL gene revealed a novel nucleotide 709 G-->T transversion present in all affected subjects and in four presymptomatic children. In familial pheochromocytoma the diagnosis of VHL should be considered, even when the formal criteria for diagnosis of the syndrome are lacking.

Adrenal Gland Neoplasms↗
PubMed1996

Renal cell carcinoma of end-stage renal disease: a histopathologic and molecular genetic study.

Renal cell carcinomas (RCC) are responsible for the deaths of 3% to 4% of patients with ESRD. The clear cell carcinoma of the kidney, which comprises 80% of sporadic RCC within the general population, shows a deletion of gene sequences in the short arm of chromosome 3 (3p) in as many as 100% of cases. The von Hippel-Lindau tumor suppressor gene at 3p25-26 is found to be mutated in the nondeleted allele in 57% of these sporadic clear cell carcinomas. This study was undertaken to determine the histopathologic types of RCC occurring in ESRD patients in the United States and to investigate the frequency with which 3p genetic changes can be found in these ESRD tumors. Seventeen end-stage kidneys containing RCC were collected from 15 ESRD patients at ten US medical centers. The tumors were classified by Thoenes' histopathologic typing. DNA extracted from paraffin blocks of tumor and nontumorous tissue was analyzed by single-stranded conformational polymorphism analysis for von Hippel-Lindau mutations and by microsatellite amplification for deletion of 3p gene sequences. Twenty-one RCC were identified in the 18 kidneys. The 21 RCC were classified histopathologically as follows: clear cell, compact, three cases; chromophilic, tubulopapillary, 15 cases; chromophilic, compact, three cases. Among the three clear cell carcinomas, one showed 3p genetic loss. None of the chromophilic RCC showed a 3p deletion and none of 19 tumors studied by single-stranded conformational polymorphism analysis disclosed von Hippel-Lindau mutations. In contrast to the general population, clear cell RCC with 3p abnormalities represent only a small proportion of the renal carcinomas in this collection of ESRD tumors. The findings indicate that the genetic changes underlying the development of most ESRD tumors are different from those occurring in sporadic clear cell RCC and do not characteristically involve the inactivation of a 3p tumor suppressor gene.

Adult↗
PubMed1996

Detection of von Hippel-Lindau disease gene mutations in paraffin-embedded sporadic renal cell carcinoma specimens.

The von Hippel-Lindau (VHL) disease gene on chromosome 3p25.5 has been cloned and shown to be mutated in the germline DNA of patients with VHL disease. In addition, approximately 60% of sporadic renal cell carcinomas (RCCs) have been shown to have a VHL gene mutation in fresh frozen tumor tissue and tumor-derived cell lines. The objective of this study was to test whether VHL gene mutations could be detected in archival sporadic RCC cases. We studied three sporadic RCCs, two oncocytomas, and the corresponding adjacent normal renal parenchyma by polymerase chain reaction and single-strand conformation polymorphism analysis using paraffin-embedded, formalin-fixed material. Tumor and normal tissue were microdissected from eosin-stained 5-microns-thick histologic sections. Mutations in exon 2 of the VHL gene were detected in all three of the sporadic RCCs but were not observed in the matched normal renal tissues or in the two oncocytomas tested. The mutations were identical to those detected in tumor cell lines from the same patients. This report represents the first detection of VHL gene mutations in sporadic RCCs in archival, paraffin-embedded tissue. A high percentage of sporadic RCCs show VHL gene mutations in fresh frozen tissue but the availability of frozen material is limited, so the evaluation of archival tumors for similar mutations should prove useful in future RCC studies. Furthermore, the results suggest that the genetic events leading to the development of clinically benign renal oncocytoma may differ from those leading to malignant RCC.

Adenoma, Oxyphilic↗
PubMed1995

Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene.

Clear cell renal carcinomas are most frequently characterized by loss of function of both copies of the von Hippel-Lindau (VHL) disease gene, suggesting that the VHL gene product plays an important role in regulating renal cell proliferation. To directly assess the function of the VHL gene product, we transfected the wild-type VHL gene into two renal carcinoma cell lines that lacked normal expression of the gene. Expression of the wild-type VHL gene led to a dramatic suppression of growth in two renal carcinoma cell lines, A498 and UMRC6 in vitro, as measured by colony formation and direct cell counting. Transfection of a naturally occurring mutant VHL gene (nucleotide 713 G to A, Arg to Gln) did not lead to growth suppression of these renal carcinoma cells, nor did transfection of the wild-type VHL gene into two non-renal tumor cell lines that expressed the endogenous wild-type VHL gene. Expression constructs, which included the first ATG at nucleotide 214, were sufficient to produce the strongest growth suppression. These experiments provide direct evidence that the VHL gene product functions to suppress the growth of renal carcinoma cells and also provide a model for mapping the domains of the VHL protein important in suppressing tumor growth.

Base Sequence↗
PubMed1995

Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations.

The von Hippel-Lindau disease (VHL) gene is a novel tumor suppressor gene that plays a role in the pathogenesis of renal cell carcinomas and hemangioblastomas of the central nervous system. To begin an evaluation of the biological functions of the VHL gene product (pVHL), we prepared bacterial fusion protein between glutathione S-transferase and wild-type or mutant pVHLs. The fusion proteins were used to identify cellular proteins that bind to pVHL in vitro. Monkey kidney cells transfected with wild-type or mutant VHL cDNAs were used to identify cellular proteins that bind to pVHL in vivo. Wild-type pVHL consistently bound two cellular proteins with apparent molecular masses of 10 and 14 kilodaltons that were designated p10 and p14, respectively. Mapping studies with a panel of VHL deletion mutant proteins demonstrated that p10 and p14 bound to a 32-amino acid peptide located in the carboxy terminal portion of pVHL. Missense mutation located within this 32-amino acid peptide abrogated the ability of the VHL protein to bind p10 and p14. Of 67 VHL families with identified germline mutations, 42 families had mutations predicted to affect the p10/p14-binding region. Maintenance of the integrity of the p10/p14-binding region appears to be essential for cellular growth regulation by pVHL.

Animals↗
PubMed1995

Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene.

The von Hippel-Lindau (VHL) disease gene is a novel multiple tumor suppressor gene which plays a causal role in the origin of some common cancers including clear cell renal carcinomas and hemangioblastomas of the central nervous system. Here we report the identification of transcription start sites and the promoter of the human VHL gene. The promoter sequence does not contain TATA and CCAAT boxes. Transcription is initiated around a putative SP1 binding site about 60 bp upstream from the first AUG codon in the VHL mRNA. Several putative transcription factor binding sites, notably for nuclear respiratory factor 1 and PAX, were found upstream of the transcription start sites. Promoter-luciferase expression constructs demonstrate, that the promoter is functional when transfected into 293 cells (transformed primary human embryonal kidney cells) and UMRC 6 renal carcinoma cells. Activity is dependent on correct orientation of the promoter. A minimal promoter region of 106 bp was delineated. A set of VHL minigenes, containing the 5' flanking VHL genomic region, was constructed and transfected into UMRC 6 cells. In these cells the level of transcription from the minigenes driven by VHL promoter was comparable with endogenous VHL expression.

Amino Acid Sequence↗
PubMed1995

Loss of heterozygosity on the short arm of chromosome 3 in sporadic, von Hippel-Lindau disease-associated, and familial pheochromocytoma.

Pheochromocytomas occur sporadically and are associated with several dominantly inherited cancer syndromes, including von Hippel-Lindau (VHL) disease. We examined 14 pheochromocytomas (four from VHL patients, nine from sporadic patients, and one from a patient with familial pheochromocytoma) for loss of heterozygosity on chromosome arm 3p by using the polymerase chain reaction and restriction fragment length polymorphisms at eight loci. Loss of heterozygosity was detected in 8 of 14 pheochromocytomas examined: in three of the four VHL-associated tumors, in four of the nine sporadic tumors, and in the familial pheochromocytoma-associated tumor. Deletion of the inherited wild-type VHL allele was demonstrated in both informative VHL-associated pheochromocytomas, demonstrating involvement of VHL in pheochromocytoma development. However, because VHL mutations have not been detected in sporadic pheochromocytomas, VHL and/or another chromosome arm 3p gene may be involved in the etiology of these tumors.

Adrenal Gland Neoplasms↗
PubMed1995

Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.

We identified a germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany. This mutation was previously identified in two VHL 2A families living in Pennsylvania (USA). All affected individuals in the 16 families shared the same VHL haplotype indicating a founder effect. This missense mutation at codon 169 (Tyr to His) would probably cause an alteration in the structure of the putative VHL protein. The association of this distinct mutation with the pheochromocytoma phenotype in VHL may help to elucidate the genetic mechanism of carcinogenesis in this multi tumor cancer syndrome.

Adrenal Gland Neoplasms↗
PubMed1995

Somatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis.

Papillary cystadenoma of the epididymis is an uncommon benign lesion that may occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease. Neither immunohistochemical studies nor molecular genetic analyses of the VHL gene have been reported previously for this lesion. The authors describe two cases of clear cell papillary cystadenoma of the epididymis, both of which were initially confused with metastatic renal cell carcinoma. Both lesions showed positive immunohistochemical staining for low and intermediate molecular weight keratins (Cam 5.2 and AE1/AE3), EMA, vimentin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin. Each was negative for CEA. Because clear cell papillary cystadenoma is similar to renal cell carcinoma histologically, and because both occur as components of the von Hippel-Lindau disease complex, the authors analyzed both cases for the presence of mutations in the VHL gene. A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single-strand conformation polymorphism analysis. Direct sequencing revealed a cytosine to thymine transition at nucleotide 694, resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3. As the VHL gene is believed to function as a tumor suppressor gene, VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis.

Adenocarcinoma, Clear Cell↗
PubMed1995

Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene.

VHL disease is a dominantly inherited familial cancer syndrome with variable expression and age-dependent penetrance. The diagnosis of isolated cases is often delayed compared with familial cases, and estimates of the new mutation rate have varied more than 20-fold. To investigate the frequency and origin of de novo VHL gene mutations we have analysed: (i) families with identical mutations to determine if there is a common haplotype, and (ii) apparent new mutation cases to determine whether the clinical diagnosis of such cases is reliable and to define the parental origin of de novo VHL gene mutations. Haplotyping of 12 VHL mutations occurring in two or more families (total 42 kindreds) revealed that for most mutations there was no evidence of a founder effect. A marked bias for a paternal origin of new mutations has been reported in other familial cancer syndromes such as neurofibromatosis type 1 (NF1), multiple endocrine neoplasia (MEN) 2B and bilateral retinoblastoma, but it is unclear whether this bias results from a greater susceptibility for mutagenesis during male gametogenesis because of the larger number of cell divisions compared with that in oogenesis, or from genomic imprinting effects. Analysis of 13 de novo VHL mutations in which the parent of origin could be established, showed no evidence for a bias for a paternal origin (seven paternal, six maternal), and differed significantly from that reported in NF1, MEN2B and bilateral retinoblastoma. This result demonstrates that an increased susceptibility to paternal allele mutation is not a universal finding in autosomal genetic diseases and that the origin of new mutations may be influenced by both genomic imprinting effects and the increased number of cell divisions in spermatogenesis compared with oogenesis.

Age Factors↗
PubMed1995

Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von Hippel-Lindau disease: clinical and molecular genetic implications.

We examined 12 patients with von Hippel-Lindau disease and renal cell carcinoma to characterize the pathological findings after renal surgery (total 161 lesions). Tissue from 15 partial nephrectomies and 1 radical nephrectomy was obtained for examination. Pathological evaluation identified 116 cystic lesions, 25 of which (21%) were malignant, and 45 solid lesions, 41 of which (91%) were renal cell carcinoma. Each kidney had a mean of 7.8 cystic and 3.0 solid lesions. Of 66 malignant lesions 35 (53%) were comprised of cells with only clear cell cytological features and 30 (45.5%) contained predominantly clear cells with scattered granular cells. One malignant lesion (1.5%) contained sarcomatoid renal cell carcinoma with clear and granular cells. Microscopic invasion of the pseudocapsule was common (13 of 25 clinically cystic tumors [52%] and 31 of 41 clinically solid lesions [76%]) but no tumor extended through the pseudocapsule. All lesions without a pseudocapsule were well circumscribed. Our study establishes the clear cell cytological features as the primary finding observed in patients with von Hippel-Lindau disease. Many cystic lesions contained renal cancer, demonstrating the need for removal of all cystic lesions when this can be safely performed. The well circumscribed nature of the tumors lends them to parenchymal sparing procedures.

Adult↗
PubMed1995

Von Hippel-Lindau syndrome.

After a decade of intensive clinical and molecular genetic efforts the von Hippel-Lindau (VHL) gene was cloned in 1993. The open reading frame encodes the putative protein of 284 amino acids. A large number of different mutations have been identified so far, including single base mutations, deletions, rearrangements and more complex mutations. So far, in about 75% of the VHL families germline mutations were detected. Geno-phenotypic comparison has revealed specific mutations with distinct manifestation patterns. Not all of the 6 classical lesions (hemangioblastoma of the CNS, retinal angiomatosis, pancreatic cysts, renal cysts and carcinoma, pheochromocytoma and epididymal cystadenoma) are present in VHL families. Pedigrees with pheochromocytoma but without renal cancer in general have point mutations. These recent results provide insight in the pathogenesis of a multiorgan cancer susceptibility tumor suppressor gene and allow determination of carrier status.

Brain↗
PubMed1995

Detection of germline mutations in the von Hippel-Lindau disease gene by the primer specified restriction map modification method.

Von Hippel-Lindau disease (VHL) is an inherited disorder characterised by a predisposition to develop tumours in the eyes, central nervous system, kidneys, and adrenal glands. Recently the VHL gene was cloned and shown to be mutated in 75% of US and Canadian VHL families. To develop simple, rapid methods for the detection of mutations found in large numbers of affected people, we designed based on the primer specified restriction site modification method. These tests have proved useful in identifying asymptomatic mutated VHL gene carriers who have the nt 505 T to C mutation or the nt 686 T to C mutation. Together with an MspI digestion test which can detect a mutation hot spot in codon 238, polymerase chain reaction/restriction endonuclease based tests can now detect VHL mutations in more than 50% of VHL type 2 families.

Base Sequence↗
PubMed1995

von Hippel-Lindau disease: genetic, clinical, and imaging features.

von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes retinal hemangioblastomas, hemangioblastomas of the central nervous system, endolymphatic sac tumors, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, and epididymal cystadenomas, among other less common manifestations. Although this entity has been recognized for almost 70 years, recent developments in the genetics and imaging of VHL disease have greatly improved understanding of the disease and its natural history. This review describes the major events that led to the discovery of the gene for VHL and will familiarize the reader with recent developments in the magnetic resonance Imaging, computed tomographic, and ultrasound findings of this entity. Despite advances in the genetic understanding of this disease, imaging techniques will continue to play a major role in the diagnosis, management, and treatment of VHL.

Adenoma, Islet Cell↗
PubMed1995

Prevalence of microscopic lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, sporadic renal cell carcinoma and no renal disease: clinical implications.

PURPOSE: We sought to describe the earliest renal lesions in patients with von Hippel-Lindau disease to gain insight into the genesis of renal neoplasms in this condition. MATERIALS AND METHODS: Grossly normal renal parenchyma from von Hippel-Lindau disease patients was examined microscopically and compared to findings in similar tissues obtained from patients with sporadic renal cancer and from autopsy subjects with no renal disease. RESULTS: Microscopic renal cystic and solid neoplasms containing only clear cell cytological features were found in patients with von Hippel-Lindau disease. Benign cysts with clear cell cytological features were found only in patients with von Hippel-Lindau disease. Benign cysts lined by cuboidal cells with eosinophilic cytoplasm, similar to renal tubular cells, were present only in patients with renal cancer. The extrapolated number of clear cell lesions in an average kidney with von Hippel-Lindau disease was estimated as 1,100 cysts (benign or atypical) with clear cell lining and 600 clear cell neoplasms. CONCLUSIONS: These findings support the hypothesis that abnormalities in the von Hippel-Lindau gene in a kidney results in the cytological cell type of clear cell renal cancer as the initial product of cellular transformation.

Adolescent↗
PubMed1995

Genetic techniques in the diagnosis of carcinomas of the kidney.

The term "carcinoma of the kidney" includes four types of cancer with distinct morphological and cytogenetic characteristics. It is likely that each type of kidney carcinoma is caused by mutation in a different gene. Families with inherited carcinomas of the kidney provide a guide to the isolation of these genes. The gene responsible for the commonest form of kidney carcinoma has been isolated by study of families with von Hippel-Lindau disease (VHL). The VHL gene is mutated in the commonest form of kidney carcinoma and in the germ line of patients with VHL. The VHL gene is a powerful tool for the study of the biology and diagnosis of kidney cancer.

DNA, Complementary↗