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Biomedical subjects

B Zbar

Publications and source records attributed to B Zbar.

At least 91 records · Page 5Linked to original sources
PubMed1995

Renal cell carcinoma. Molecular genetics and clinical implications.

The combined efforts of a number of investigators have led to the identification of the VHL gene, which appears to function as a tumor suppressor gene and is implicated in both sporadic and familial forms of RCC. These findings should increase our understanding of the molecular biology of this malignancy; however, there is much work to be done. Identification of the mechanism of inactivation of the VHL gene, as well as the structure and function of the VHL gene product, ultimately may provide clinicians with greater understanding of this malignancy as well as with methods for earlier diagnosis. The role of other tumor suppressor genes, such as p53, is incompletely understood. It is hoped that the techniques that have been applied to the study of RCC also will result in advances in our knowledge of other urologic malignancies.

Aged↗
PubMed1995

Hereditary papillary renal cell carcinoma: clinical studies in 10 families.

We recently described a 3-generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Possibly family 150 is an isolated occurrence, a reflection of some as yet unknown environmental factor. Alternatively, family 150 may represent a distinct class of inherited cancer. To distinguish between these 2 possibilities we sought additional families with papillary renal cell carcinoma and we identified 9 with members affected with papillary renal cell carcinoma. There were 29 affected male and 12 affected female subjects (ratio 2.41:1), including affected members of family 150. Papillary renal cell carcinomas were often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal cell carcinoma families. The penetrance, the proportion of obligate gene carriers that showed clinical evidence of the disease, was reduced. The median survival of affected individuals was 52 years. The results support the concept that the predisposition to develop papillary renal cell carcinomas may be inherited and that hereditary papillary renal cell carcinoma constitutes a distinct class of inherited cancer.

Adolescent↗
PubMed1995

Genetics of renal-cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis.

Using a genetic linkage-based positional cloning approach the VHL gene was identified at chromosome 3p25.5. VHL is mutated in the germlines of affected individuals, and in VHL-associated tumors the mutation is almost always exposed by virtue of chromosomal deletion of the inherited wild-type allele. VHL is also frequently mutated in sporadic, nonpapillary RCC and in familial RCC. This was predicted because such tumors are histologically similar to VHL-associated renal tumors. Knowledge that VHL plays a critical role in sporadic RCC should aid in the future diagnosis and treatment of this malignancy. Detailed analyses of the biology of individual mutations will be required to determine whether the inherited VHL mutations or acquired sporadic mutations cause loss of protein function or have dominant-negative affects. However, the nature of the VHL protein is at present unclear and a complete understanding its function will only be expected after the cloning of the full-length gene.

Carcinoma, Renal Cell↗
PubMed1995

Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a familial cancer syndrome that has a dominant inherited pattern which predisposes affected individuals to a variety of tumours. The most frequent tumors are hemangioblastomas of the central nervous system and retina, renal cell carcinoma (RCC), and pheochromocytoma. The recent identification and characterization of the VHL gene on human chromosome 3p and mutational analyses confirms the VHL gene functions as a classical tumor suppressor. Not only are mutations in this gene responsible for the VHL syndrome, but mutations are also very frequent in sporadic RCC. MATERIALS AND METHODS: VHL expression in human kidney and during embryogenesis, was analyzed by in situ mRNA hybridization with 35S-labeled antisense VHL probes, derived from human and mouse cDNAs, on cryosections of human fetal kidney and paraffin sections of murine embryos. RESULTS: In human fetal kidney, there was enhanced expression of VHL within the epithelial lining of the proximal tubules. During embryogenesis, VHL expression was ubiquitous in all three germ cell layers and their derivatives. Expression occurred in the cerebral cortex, midbrain, cerebellum, retina, spinal cord, and postganglionic cell bodies. All organs of the thoracic and abdominal cavities expressed VHL, but enhanced expression was most apparent in the epithelial components of the lung, kidney, and eye. CONCLUSIONS: In human fetal kidney, the enhanced epithelial expression of the VHL gene is consistent with the role of this gene in RCC. There is widespread expression of the VHL gene during embryogenesis, but this is pronounced in areas associated with VHL phenotypes. These findings provide a histological framework for investigating the physiological role of the VHL gene and as basis for further mutational analysis.

Animals↗
PubMed1995

Von Hippel-Lindau disease and sporadic renal cell carcinoma.

The VHL gene, isolated by positional cloning, encodes a protein of 284 aminoacids that has no homology with other proteins in the databases. The nucleotide sequence lacks domains that would suggest (a) a DNA binding protein, (b) nuclear localization, (c) enzymatic activity or (d) membrane localization. Studies are in progress on the size and cellular localization of the VHL protein and how it may function in growth regulation. How mutations in this small protein lead to a specific tumour spectrum presents an enormous research challenge. Germline mutations in the VHL gene are heterogeneous, and the resulting heterogeneity of mutations in the VHL protein that lead to disease suggests a protein whose function can be compromised by mutations over a large area. Study of the germline mutations and correlation with disease patterns provide the basis for a new clinical classification of von Hippel-Lindau disease. Somatic VHL mutations and hypermethylation of the VHL gene are found in some 75-80% of sporadic clear cell renal carcinomas. About 20% of clear cell renal carcinomas show neither VHL gene mutation or hypermethylation. Whether other chromosome 3 tumour suppressor genes have a pathogenetic role in clear cell renal carcinoma remains to be determined. Sorting out the contributions of different tumour suppressor genes to the pathogenesis of clear cell renal carcinomas will require assays demonstrating somatic mutation of candidate genes and functional assays to determine whether replacement of the mutant gene is associated with suppressed tumour growth.

Adrenal Gland Neoplasms↗
PubMed1994

Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma.

Mutational inactivation and allelic loss of the von Hippel-Lindau (VHL) gene appear to be causal events for the majority of spontaneous clear-cell renal carcinomas. We now show that hypermethylation of a normally unmethylated CpG island in the 5' region provides another potentially important mechanism for inactivation of the VHL gene in a significant portion of these cancers. This hypermethylation was found in 5 of 26 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with VHL hypermethylation had no detectable mutations, whereas one had a missense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in this 5' CpG island, none of the 5 tumors expressed the VHL gene. In contrast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene. These findings suggest that aberrant methylation of CpG islands may participate in the tumor-suppressor gene inactivations which initiate or cause progression of common human cancers.

Adenocarcinoma, Clear Cell↗
PubMed1994

Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.

We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL) tumor suppressor gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positive cases in single strand conformational polymorphism analyses were further characterized by direct sequencing. Somatic mutations were detected in 22 (56%) of 39 clear cell renal carcinomas including 15 deletions, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Nineteen of these mutations predicted to produce truncation of the VHL protein. These mutations mainly occurred in the last one-third region of exons 1, 2, and 3. In addition, loss of heterozygosity of the VHL gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas. No somatic mutations were detected in 8 non-clear cell carcinomas. These results show that the VHL tumor suppressor gene is one of the major tumor suppressor genes in human renal cell carcinomas, especially in the clear cell subtype renal cell carcinoma. Clear cell carcinoma might be distinguished from other pathological types of renal cell carcinomas by molecular genetic techniques.

Base Sequence↗
PubMed1994

Loss of heterozygosity on the short arm of chromosome 3 in mesothelioma cell lines and solid tumors.

Cytogenetic analysis of mesothelioma cell lines and solid tumors has documented non-random chromosomal abnormalities on the short arm of chromosome 3 from 3p14 to 3p25. We therefore examined nine mesothelioma cell lines, their corresponding tumors, and 15 additional mesothelioma tumors for loss of heterozygosity on 3p from 3p13 to 3p25.5 by polymerase chain reaction and restriction fragment length polymorphism analysis at 8 loci: D3S3, D3S30, D3S6, D3S2, D3S32, D3F15S2, THRB, and VHL. Loss of heterozygosity was documented by loss of one of two alleles in the tumor DNA whose corresponding normal DNA was heterozygous and was documented in four of nine mesothelioma cell lines and six of 15 mesothelioma tumors or a total of 42% of the mesotheliomas evaluated. This study suggests the involvement of a gene on the short arm of chromosome 3 in the development of mesotheliomas.

Alleles↗
PubMed1994

The use of molecular genetic analysis in the diagnosis of renal cell carcinoma.

The most common genetic aberration seen in nonpapillary renal cell carcinoma is believed to be the loss or inactivation of allelic material on the short arm of chromosome 3 (3p). Two patients underwent nephrectomy at our institution, each initially receiving a histologic diagnosis of renal cell carcinoma. Molecular analysis of these tissues revealed no genetic deletion on 3p, prompting further histologic and immunohistochemical evaluation of the original specimens. These additional studies confirmed alternate histologies other than renal cell carcinoma in each case. These data suggest that the loss of genetic material on the short arm of chromosome 3 may be specific for nonpapillary renal cell carcinoma. Molecular analysis may prove to be a useful adjunct in establishing the diagnosis in renal neoplasms with equivocal histologies.

Adult↗
PubMed1994

Hereditary papillary renal cell carcinoma.

We describe a 3 generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Multiple tumors of varying size were present in both kidneys of affected family members. The disorder was not linked to polymorphic markers on chromosome 3p and there was no loss of heterozygosity at loci on 3p in renal tumors. The results suggest the presence of a renal cell carcinoma gene not located on 3p that predisposes to renal cell carcinoma with a distinct histological appearance. The inherited disorder in this family appears to be different from recognized hereditary cancer syndromes.

Adolescent↗
PubMed1994

Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene.

Von Hippel-Lindau disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. A cDNA (g7) which detects frequent genomic rearrangements in VHL disease patients on Southern analysis, and contains the partial coding sequence of the VHL gene has been isolated recently. To characterise the nature of the genomic rearrangements in VHL disease we initially screened 116 patients with VHL disease and identified 22 patients (19%) with abnormal fragments in EcoR1 digested DNA probes with g7. We then established that the coding sequence contained within g7 is represented in 3 exons, and design exon specific probes to investigate the 22 patients with genomic rearrangements. All 22 patients were demonstrated to have germline deletions, but the deletions were heterogeneous with 7 patients having deletions confined to the 5' exon 1, and 8 with nonoverlapping deletions of exon 3. In 7 unrelated patients, including 2 new mutations, the germline deletions were similar in size and position. There was no relationship between the clinical phenotype and the deletion of individual exons. Although phaeochromocytoma was less frequent in kindreds with germline deletions than those without detectable deletions, the difference was not statistically significant (1/19 versus 16/72 respectively, chi 2 = 1.84 p > 0.1).

Amino Acid Sequence↗
PubMed1994

Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal haemangioblastoma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. We have previously detected large germline deletions by Southern analysis and pulsed field gel electrophoresis in 19% and 3% of VHL patients respectively. We have now investigated 94 VHL patients without large deletions for intragenic mutations using single strand conformation polymorphism and heteroduplex analysis. Forty different mutations were identified in 55 unrelated kindreds. A wide variety of mutations were detected including missense (n = 19), nonsense (n = 6), frameshift deletions or insertions (n = 12), in frame deletions (n = 2) and a splice donor site mutation (n = 1). The two most frequent mutations, were missense mutations at codon 238 (Arg-->Gln and Arg-->Trp) and were detected in five and four unrelated kindreds, respectively. VHL disease shows marked phenotypic variability and although phaeochromocytoma occurs in only about 7% of patients, marked interfamilial differences are observed. We examined the relationship between VHL gene mutations and phenotype in 65 kindreds. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without phaeochromocytoma but only two of 12 families with phaeochromocytoma (chi 2 = 8.58; P < 0.01). Of 12 families with phaeochromocytoma 10 had missense mutations compared with 13 of 53 kindreds without phaeochromocytoma (chi 2 = 12.33; P < 0.001). In particular, substitution of an arginine at codon 238 (Arg-->Trp or Arg-->Gln) was associated with a high risk (62%) of phaeochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines.

The deletion of the short arm of chromosome 3 is frequently observed in lung cancer. To determine whether the von Hippel-Lindau (VHL) disease tumor suppressor gene located at 3p25 is responsible for oncogenesis in lung cancer, we searched the known open reading frame using the single-strand conformation polymorphism (SSCP) technique for mutations in the VHL gene in 72 cancer cell lines including small cell (SCLC) and non-small cell (NSCLC) lung cancers, carcinoids, and mesotheliomas. SSCP analysis showed that four cell lines have altered SSCP patterns within the coding region and one in an intron of the VHL gene. SCLC line NCI-H1672 had a somatic mutation, G to A at nucleotide (nt) 530, leading to amino acid substitution (glycine to aspartic acid) compared to normal DNA from the same patient. Mesothelioma line NCI-H28 had T to A mutation at nt 479 leading to leucine to histidine amino acid change. We found one frequent polymorphism A (0.72) or G (0.28) at nt 19 resulting in either serine or glycine at this position, changes also found in normal peripheral blood cell DNA, often in a heterozygous state. In addition, we found single rare polymorphisms which did not alter the coding region including: C to G at nt 396, G to T at nt 843, and C to T change in an intron. These results suggest that the VHL gene is only rarely mutated in thoracic malignancies.

Base Sequence↗
PubMed1993

Clinical and molecular analyses of deletion 3p25-pter syndrome.

Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM).

Abnormalities, Multiple↗
PubMed1993

Clinical and genetic studies of renal cell carcinomas in a family with a constitutional chromosome 3;8 translocation. Genetics of familial renal carcinoma.

OBJECTIVE: To describe the clinical course and genetic studies of renal carcinoma in members of a family with the constitutional chromosome translocation, t(3;8) (p14;q24). DESIGN: A follow-up study that updates our 1979 report of renal carcinoma in 10 of these relatives. SETTING: A cancer center and university hospital. PATIENTS: Members of the family, including five carriers of the 3;8 translocation who were in remission of renal cancer. MEASUREMENTS: Clinical follow-up of the family and genetic analyses of the renal cancer specimens of three patients. RESULTS: Renal carcinoma recurred in all five patients in the family at 1 to 16 years of follow-up. Three patients have died of renal cancer, and two are in a second remission. The renal cancers from three family members consistently reveal loss of the entire derivative chromosome 8, which bears the chromosome 3p segment spanning band p14 to the telomere. In contrast, no genetic change was detected in the derivative chromosome 3 or in normal chromosomes 3 and 8. CONCLUSIONS: This family illustrates the importance of clinical follow-up of patients with a hereditary cancer that can develop at multiple foci and recur over time. The inherited 3;8 translocation and loss of the translocated distal chromosome 3p in tumor specimens of family members may help localize the gene or genes involved in the pathogenesis of both familial and sporadic renal carcinoma.

Adult↗