Comorbid VHL and SCA2 mutations in a large kindred: confounding diagnosis of neurological dysfunction caused by CNS VHL vascular tumours versus SCA2 atrophic neurodegeneration.
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Adult↗
Biomedical subjects
W M Linehan
Publications and source records attributed to W M Linehan.
The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis.
Here we report the genetic characterization of immortalized prostate epithelial cells before and after conversion to tumorigenicity using molecular cytogenetics and microarray technology. We were particularly interested to analyze the consequences of acquired chromosomal aneuploidies with respect to modifications of gene expression profiles. Compared with nontumorigenic but immortalized prostate epithelium, prostate tumor cell lines showed high levels of chromosomal rearrangements that led to gains of 1p, 5, 11q, 12p, 16q, and 20q and losses of 1pter, 11p, 17, 20p, 21, 22, and Y. Of 5700 unique targets on a 6.5K cDNA microarray, approximately 3% were subject to modification in expression levels; these included GRO-1, -2, IAP-1,- 2, MMP-9, and cyclin D1, which showed increased expression, and TRAIL, BRCA1, and CTNNA, which showed decreased expression. Thirty % of expression changes occurred in regions the genomic copy number of which remained balanced. Of the remainder, 42% of down-regulated and 51% of up-regulated genes mapped to regions present in decreased or increased genomic copy numbers, respectively. A relative gain or loss of a chromosome or chromosomal arm usually resulted in a statistically significant increase or decrease, respectively, in the average expression level of all of the genes on the chromosome. However, of these genes, very few (e.g., 5 of 101 genes on chromosome 11q), and in some instances only two genes (MMP-9 and PROCR on chromosome 20q), were overexpressed by > or =1.7-fold when scored individually. Cluster analysis by gene function suggests that prostate tumorigenesis in these cell line models involves alterations in gene expression that may favor invasion, prevent apoptosis, and promote growth.
Aneuploidy↗
Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.
Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.
Abnormalities, Multiple↗
Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma.
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Adrenal Gland Neoplasms↗
Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.
Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.
Adrenal Gland Neoplasms↗
Detection of loss of heterozygosity at chromosome 3p25-26 in primary and metastatic ovarian clear-cell carcinoma: utilization of microdissection and polymerase chain reaction in archival tissues.
Loss of heterozygosity (LOH) at the 3p region is found in up to 50% of epithelial ovarian neoplasms. The von Hippel-Lindau (VHL) gene at the 3p25 locus is one of the tumor-suppressor genes located at 3p. The role, if any, of the VHL gene locus is not clear in ovarian carcinogenesis. We analyzed primary and metastatic ovarian clear-cell carcinomas (OCCC) for LOH at 3p25 to determine its frequency and its diagnostic utility as an adjunctive tool in the differential diagnosis of metastatic clear-cell carcinomas. Microdissection followed by single-step DNA extraction and polymerase chain reaction (PCR) amplification, using two polymorphic markers flanking the VHL gene locus, was done on archival histology and cytology samples from 9 patients with metastatic OCCC. Of the informative cases, 43% of the metastatic and 50% of the primary OCCC showed LOH. LOH at the VHL gene locus is not uncommon in clear-cell ovarian carcinoma. LOH at 3p25 in cytologic specimens may be a valuable adjunct in the diagnosis of OCCC metastasis in cytologically equivocal cases. OCCC should enter the differential in clear-cell carcinomas of unknown primary that show LOH at 3p25. Published 2001 Wiley-Liss, Inc.
Adenocarcinoma, Clear Cell↗
Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease.
Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1-2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21-22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs. Published 2001 Wiley-Liss, Inc.
Adult↗
Partial adrenalectomy in patients with multiple adrenal tumors.
Most adrenal tumors are found incidentally and appear as small solitary nodules on abdominal imaging. Occasionally, work-up demonstrates multifocal or bilateral adrenal tumors. Certain patients are predisposed to multiple lesions, such as those with hereditary forms of pheochromocytoma as seen in von Hippel-Lindau disease, multiple endocrine neoplasia type II, and von Recklinghausen's disease. Partial rather than total adrenalectomy should be considered for these patients in an attempt to preserve endogenous adrenocortical function. Partial adrenalectomy has also been used to resect other types of adrenal tumors, especially in patients with a solitary adrenal gland. A discussion of the indications for partial adrenalectomy and of the surgical technique follows.
Adenoma↗
Comorbid genetic diseases, von Hippel-Lindau disease and spinocerebellar ataxia type 2, confounding the diagnosis of cerebellar dysfunction in an adolescent.
The authors report a 15-year-old female who presented with difficulties in ambulation as well as difficulties with balance and penmanship. She had a known genetic risk of von Hippel-Lindau (VHL; MIM 193300) disease, with a unique VHL mutation, but had no tumors of the brain or spine to explain her symptoms. Laboratory analysis of peripheral blood lymphocytes was targeted at genetic loci associated with ataxic disorders. Allelic expansion of the ataxin-2 gene was identified. Spinocerebellar ataxia type 2 (SCA2) was diagnosed as a comorbid genetic condition in this patient.
Adolescent↗
Pigmented renal clear cell carcinoma with melanocytic differentiation.
Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney, and its incidence has been steadily rising. RCC consists of several subtypes, each of which has its own clinical features, and cytogenetic and molecular characteristics. Recognizing histologic patterns of RCC is important not only for correct diagnosis, but also for providing insight into the biological behavior of the tumor and subsequent appropriate medical care for the patient. Pigments other than hemosiderin has been observed in RCC, but none of them have been proved to be melanin. Melanotic tumors, either primary or metastatic, are rare in the kidney. We present an unusual case of melanin-pigmented clear cell RCC with melanocytic differentiation, an unusual variant that may lead to errors in diagnosis and treatment.
Adenocarcinoma, Clear Cell↗
Intraoperative ultrasound during renal parenchymal sparing surgery for hereditary renal cancers: a 10-year experience.
PURPOSE: We review our 10-year experience with intraoperative ultrasound during renal parenchymal sparing surgery in patients with hereditary renal cancers. MATERIALS AND METHODS: Between 1991 and 2000, 68 nephron sparing procedures were performed on 26 women and 27 men, all but 1 of whom had a hereditary predisposition to renal cancer, for example von Hippel-Lindau, hereditary papillary renal cancer. Intraoperative ultrasound was performed after the surgeon removed all visible or palpable lesions. High frequency transducers (7 MHz.) and color Doppler were used in all cases. Lesions were characterized as simple cysts, complex cysts or solid masses, and were recorded on a map. RESULTS: A total of 935 lesions (mean 12.8 lesions per kidney) were removed in 68 nephron sparing operations performed on 53 patients. Of these lesions 870 were removed without while 65 required intraoperative ultrasound. In 17 of 68 (25%) procedures intraoperative ultrasound identified renal cancers that were not detectable by the surgeon. Mean tumor size of ultrasound detected lesions was 1.0 cm. (range 2 mm. to 4 cm.). Of the 32 cystic lesions identified by intraoperative ultrasound 5 contained renal carcinoma, and 29 of the 33 solid renal masses were renal cell carcinomas. During reoperations ultrasound enabled the surface of the kidney to be evaluated even when it was inaccessible due to scar tissue or adherent perinephric fat. CONCLUSIONS: Intraoperative ultrasound can be performed after all visible lesions have been removed and identifies additional tumors in 25% of patients with hereditary renal cancer, thus ensuring that as many tumors as possible have been removed during renal parenchymal sparing surgery.
Carcinoma, Renal Cell↗
The genetic basis of renal epithelial tumors: advances in research and its impact on prognosis and therapy.
The genetics of renal cell carcinoma continues to elucidate the pathways of kidney tumorigenesis. The relationship between the VHL gene and clear cell carcinoma, MET and papillary carcinoma, and the families of genes that they regulate, continues to be unraveled. New hereditary kidney cancer syndromes, like familial oncocytoma and the Birt-Hogg-Dubé syndrome, have been identified and the search for the genes that cause them is under way. Researching the genetics of these disorders is essential for an understanding of sporadic kidney cancer genetics. This chapter will review the current knowledge of the hereditary kidney cancer syndromes, the genes that cause them, new advances in genetic research and techniques, and how this information impacts upon diagnostic, prognostic, and therapeutic methods of the future.
Carcinoma, Renal Cell↗
Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes.
This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.
Adolescent↗
Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience.
PURPOSE: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, the Birt-Hogg-Dubé syndrome and familial renal oncocytoma are familial renal tumor syndromes. These hereditary disorders are noteworthy for the development of multiple bilateral renal tumors and the risk of new tumors throughout life. One management strategy is observation of solid renal tumors until reaching 3 cm, then performing parenchymal sparing surgery. We present a 5-year update on our experience. MATERIALS AND METHODS: From May 1988 to October 1998, 49 patients with hereditary renal cell carcinoma, including von Hippel-Lindau disease in 44, hereditary papillary renal cell carcinoma in 4 and the Birt-Hogg-Dubé syndrome in 1, and 1 with familial renal oncocytoma underwent exploration to attempt renal parenchymal sparing surgery. Patients were followed prospectively with periodic screening for recurrence, metastasis and loss of renal function. Median followup was 79.5 months (range 0.7 to 205). RESULTS: A total of 50 patients underwent 71 operations resulting in unilateral nephrectomy in 6, bilateral nephrectomy in 1 and partial nephrectomy in 65, with 1 to 51 tumors removed from each kidney (mean 14.7). Mean patient age was 39.5 years (range 18 to 70). Of the 65 (40%) partial nephrectomies 26 were performed with cold renal ischemia. Mean blood loss was 2.9 +/- 0.5 l (range 0.15 to 23). Postoperative complications included renal atrophy in 3 patients. Mean preoperative serum creatinine was 1.05 +/- 0.03 mg/dl (range 0.6 to 1.8), and postoperative creatinine was 1.06 +/- 0.04 mg/dl (range 0.6 to 2.0). No patient who underwent renal parenchymal sparing surgery required renal replacement therapy. Metastatic disease developed in 1 patient with a 4.5 cm renal tumor. CONCLUSIONS: Parenchymal sparing surgery with a 3 cm threshold in patients with hereditary renal cancer appears to be an effective therapeutic option to maximize renal function while minimizing the risk of metastatic disease.
Adolescent↗
Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium.
PURPOSE: The NKX-3.1gene is an androgen regulated prostate specific homeobox gene that is believed to have a vital role in normal prostate development. In mice the homologue NKx3.1 is exclusively expressed in prostate epithelium. In humans NKX3.1 expression is also restricted to the prostate but to our knowledge the cellular location has not been described. Furthermore, since NKX3.1 maps to chromosomal band 8p21, a region with high loss of heterozygosity in prostate cancer, the gene has been proposed to have tumor suppressor function. In this study we demonstrate that in human prostates NKX3.1 is expressed exclusively in secretory epithelial cells and the level of NKX3.1 expression remains invariant in normal tissue and in tissue showing various grades of prostate cancer. In the 19 cases examined the DNA sequences of the NKX3.1 gene were identical and no mutation was detected. MATERIALS AND METHODS: Frozen tissue from patients who underwent radical prostatectomy was used for this study. For in situ hybridization experiments a 377 bp fragment corresponding to a portion of the 3' untranslated region of the NKX3.1 gene was amplified by polymerase chain reaction and cloned into the pCRII plasmid vector Invitrogen. Antisense or sense [33P] uridine triphosphate labeled RNA probes were generated with SP6 or T7 RNA polymerase and hybridized to the tissue sections. Slides were exposed to photographic emulsion and visualized on autoradiography. Laser capture microdissection was performed to procure pure populations of malignant epithelium. DNA was isolated by digesting samples in proteinase K buffer. Polymerase chain reaction and direct sequencing was performed using standard protocols. RESULTS: In vitro hybridization showed that NKX3.1 expression was restricted to secretory epithelial cells within benign prostate glands. No expression was detected in stroma or infiltrating lymphocytes. NKX3.1 was expressed in all grades of malignant epithelium in all 25 cases examined. Direct sequencing of the coding region of NKX3.1 revealed the wild-type sequence in all 18 microdissected cancers analyzed. CONCLUSIONS: Based on our studies we propose that NKX3.1 gene expression is restricted to benign and malignant secretory epithelium within the prostate but NKX3.1 does not appear to be a classic tumor suppressor gene responsible for prostate cancer initiation. These findings are consistent with the role of NKX3.1 in the development of normal prostate epithelium and maintenance of normal secretory function. Thus, NKX3.1 may represent a useful molecular marker for benign and malignant prostate epithelium.
DNA Mutational Analysis↗
Screening for and identification of novel agents directed at renal cell carcinoma.
We were interested in identifying novel agents for renal cell carcinoma (RCC) by screening for activities that model renal tumor biology. Searching for relative renal cell sensitivity and leukemia insensitivity among cytotoxicity profiles in the NCI Drug Screen database, we identified 16 potential agents with renal selectivity. We evaluated the agents in 10 RCC cell lines (of primary and metastatic origin) isolated from 5 patients. The 50% inhibitory concentrations (IC50) in these cell lines ranged from 0.019 +/- 0.013 to 11.4 +/- 0.55 microM and were comparable with values obtained with renal cell lines in the NCI Drug Screen panel. Because RCC are slowly growing tumors, we evaluated the compounds on rapidly (27% S phase) or slowly (6% S phase) growing cells. In contrast to doxorubicin, where cytotoxicity was restricted to rapidly proliferating cells, three compounds (NSC 280074, 281613, and 281817) were more cytotoxic in slowly proliferating cells. NSC 72151 and 268965 were equitoxic for both populations. NSC 94889, 638850, and 630938 were more cytotoxic in rapidly growing cells. In in vitro time exposure studies, four compounds, NSC 268965, 280074, 281613, and 281817, were maximally cytotoxic with as little as 3 h exposure time. From an analysis comparing the p53 genotype of the 60 cell lines of the National Cancer Institute (NCI) Drug Screen with the cytotoxicity profiles for the 16 putative renal compounds, 13 compounds were classified as likely to be indifferent to p53 status. We also developed a panel specificity detection method for the NCI Drug Screen database to evaluate the prevalence of renal sensitive compounds. Of the 16 studied compounds, 14 were among those identified as renal sensitive by the statistical analysis. Lastly, we found reduced tumor growth in mice with established renal human tumor xenografts after treatment with two of the renal active compounds. These studies describe compounds with potential renal activity that are candidates for preclinical development for renal cell carcinoma.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Parenchymal sparing surgery in a patient with multiple bilateral papillary renal cancer.
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Carcinoma, Papillary↗
Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma.
PURPOSE: Patients with metastatic renal cell carcinoma have a reported 5-year survival of 0% to 20%. The ability to predict which patients would benefit from nephrectomy and interleukin-2 (IL-2) therapy before any treatment is initiated would be useful for maximizing the advantage of therapy and improving the quality of life. MATERIALS AND METHODS: A retrospective analysis of the x-rays and charts of patients treated at the National Institutes of Health Surgery Branch between 1985 and 1996, who presented with metastatic renal cancer beyond the locoregional area and the primary tumor in place, was performed. Preoperative computerized tomography or magnetic resonance imaging, or radiological reports if no scans were available, were used to obtain an estimate of the volume of retroperitoneal lymphadenopathy. Operative notes were used to evaluate whether all lymphadenopathy was resected or disease left in situ, or if any extrarenal resection, including venacavotomy, was performed. Mean survival rate was calculated from the time of nephrectomy to the time of death or last clinical followup. If patients received IL-2 therapy, the response to treatment was recorded. Mean survival and response rate for IL-2 were compared among patients in 3 separate analyses. Patients without preoperatively detected lymphadenopathy were compared with those with at least 1 cm.3 retroperitoneal lymphadenopathy. Also, the patients who had detectable lymphadenopathy were divided into subgroups consisting of all resected, incompletely resected, unresectable and unknown if all disease was resected. Each subgroup was compared with patients without detectable preoperative lymphadenopathy. Patients with less than were compared to those with greater than 50 cm.3 retroperitoneal lymphadenopathy. Patients undergoing extrarenal resection at nephrectomy (complex surgery) due to direct invasion of the tumor into another intra-abdominal organ were compared with those undergoing radical nephrectomy alone, regardless of lymph node status. Statistical analysis was done with the Mantel-Cox test for comparison of survival on Kaplan-Meier curves and with Fisher's exact test for response rates for IL-2. RESULTS: A total of 154 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy as preparation for IL-2 based regimens. There were 82 patients with metastatic renal cell carcinoma and no preoperative retroperitoneal lymphadenopathy who survived longer (median 14.7 months) than the 72 with lymphadenopathy (median 8.5, p = 0.0004). Patients with incompletely resected, unresectable or an unknown volume resected had decreased survival compared to those with no retroperitoneal lymphadenopathy. A multivariate analysis of survival was performed evaluating the known prognostic indicators, performance status and tumor burden, as represented by the number of organs involved with metastases, and the new prognostic factor, lymphadenopathy. Lymphadenopathy was more closely associated with survival than performance status, and appeared to be a new prognostic variable. Patients with and without retroperitoneal lymphadenopathy at initial presentation had similar rates for treatment with IL-2 (54% for both groups). Of the 82 patients with no lymphadenopathy 11 (13%) had long-term survival greater than 5 years. Of the 6 complete responses to IL-2, 5 occurred in this group. Only 1 other patient with incompletely resected retroperitoneal lymphadenopathy survived longer than 5 years. No significant difference in survival was seen between patients who did or did not undergo complex surgery. CONCLUSIONS: Patients who presented with metastatic renal cancer and retroperitoneal lymphadenopathy had a shorter survival than those with no detectable retroperitoneal lymphadenopathy. It is warranted to continue to perform complex extrarenal resection during nephrectomy since no significant difference in the response rate for IL-2 or mean survival compared with those of patients undergoing nephrectomy alone is currently detectable.
Adult↗