Association of VHL Genotype With Pancreatic Neuroendocrine Tumor Phenotype in Patients With von Hippel-Lindau Disease.
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ABSTRACT:
SUBMITTER: Tirosh A
PROVIDER: S-EPMC5833646 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
Association of VHL Genotype With Pancreatic Neuroendocrine Tumor Phenotype in Patients With von Hippel-Lindau Disease.
Tirosh Amit A Sadowski Samira M SM Linehan W Marston WM Libutti Steven K SK Patel Dhaval D Nilubol Naris N Kebebew Electron E
JAMA oncology 20180101 1
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Project description:PurposeData regarding the clinical management and follow-up of pancreatic neuroendocrine tumors (PanNETs) associated with Von Hippel-Lindau (VHL) syndrome are limited. This study aimed to assess clinical presentation, genotype-phenotype correlations, treatment and prognosis of PanNETs in a series of VHL syndrome patients.MethodsRetrospective analysis of data of patients observed between 2005 and 2020.ResultsSeventeen patients, including 12 probands and 5 relatives (mean age 30.8 ± 18.4; 7 males), were recruited. PanNETs were found in 13/17 patients (77.5%) at a median age of 37 years: 4/13 (30.7%) at the time of VHL diagnosis and 9 (69.3%) during follow up. Six (46.1%) PanNET patients underwent surgery, whereas seven were conservatively treated (mean tumor diameter: 40 ± 10.9 vs. 15 ± 5.3 mm respectively). Four patients (30.7%) had lymph node metastases and a mean tumor diameter significantly larger than the nonmetastatic PanNETs (44.2 ± 9.3 vs. 17.4 ± 7 mm, p = 0.00049, respectively). Five (83.3%) operated patients had stable disease after a median follow up of 3 years whereas one patient showed liver metastases. Six (85.7%) non-resected PanNETs were stable after a median follow-up of 2 years, whereas one patient developed a new small PanNET and a slight increase in diameter of a pre-existing PanNET. No correlation was found between the type of germline mutation and malignant behavior of PanNETs.ConclusionsPanNETs are a common disease of the VHL syndrome and can be the presenting feature. Tumor size rather than genetic mutation is a prognostic factor of malignancy.
| S-EPMC8440302 | biostudies-literature
Project description:Purposevon Hippel-Lindau (VHL) disease is a dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene. This study was conducted to establish genotype-phenotype correlations between the positions of disease-causing missense mutations and the ocular phenotypes of VHL disease.MethodsParticipants with clinically defined VHL disease and documented germline missense mutations in the VHL gene were identified in a cross-sectional study (n=412). Statistical analysis was used to correlate the position of the missense mutation in either the alpha- or beta-domain of the VHL protein with the ocular disease phenotype.ResultsMissense mutations among study participants were located in 47 of the 213 possible codons in the VHL gene. Almost all mutations (98.5%) were located in one of two structural domains of the VHL protein: the alpha- and beta-domains. alpha-Domain mutations were significantly associated with a higher prevalence of retinal capillary hemangioblastomas (RCHs) compared with the beta-domain mutations (P=0.016). Among patients with RCHs, the prevalence of the lesions in the juxtapapillary position was also significantly higher in patients with alpha-domain mutations (P=0.0017). Conversely, beta-domain mutations correlated with a higher prevalence of peripherally located RCHs (P=0.0104).ConclusionsThe location of missense mutations in the VHL gene correlates significantly with the prevalence and phenotype of ocular disease, and as such, influences the risk of visual loss in affected patients. These genotype-phenotype correlations can assist in the prognostic counseling and follow-up of VHL patients and may provide a basis for molecular inferences on ocular VHL disease pathogenesis.
| S-EPMC2941163 | biostudies-literature
Project description:The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in alpha-cells or an insulin promoter in beta-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.
| S-EPMC2660574 | biostudies-literature
Project description:Context:Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective:To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design:A prospective natural history study. Setting:The National Institutes of Health clinical center. Patients:Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention:In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure:Rates of metastases, surgical intervention, and disease progression. Results:Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions:Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.
| S-EPMC6276699 | biostudies-literature
Project description:von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082-2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419-5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392-15.724, p = 0.013; HR = 4.683, 95% CI 2.515-8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.
| S-EPMC5503545 | biostudies-literature
Project description:BackgroundClassical von Hippel Lindau (VHL) disease/syndrome includes CNS hemangioblastoma, renal or pancreatic cysts, pheochromocytoma, renal carcinoma and exodermic cystadenoma. The syndrome is caused by mutation of VHL tumor suppressor gene. The most prevalent mutations are present in VHL syndrome. To date, > 500 mutations of gene related to the progression of VHL syndrome have been reported. VHL gene mutation presented in single lung or pancreatic tumor has been reported occasionally, but there is no report of both.MethodsIn this paper, we used CT scan, pathological and genetic examination methods to diagnose a rare atypical VHL syndrome.ResultsWe reported a rare case of atypical VHL syndrome with authenticated VHL mutation at p.Arg167Gln, that was associated with not only bilateral pheochromocytoma but also lung carcinoid and neuroendocrine tumor of pancreas. Based on literature reviews, the patient was recommended to be further subjected to octreotide-based radionuclide therapy.ConclusionsCombined with gene detection and clinical diagnosis, we found the inherent relationship between VHL genotype and phenotype, and constructed the standard diagnosis and treatment process of disease with rare VHL mutation from the perspective of gene therapy.
| S-EPMC8684656 | biostudies-literature
Project description:ObjectivesTo characterize the germline mutations found in a large population of persons having von Hippel-Lindau (VHL) disease mutations with the clinical characteristics of associated retinal capillary hemangioblastomas (RCHs), to measure the prevalence of RCHs among patients with VHL disease generally and specifically for each genotype category, to establish genotype-phenotype correlations between genotype category and phenotypic features of ocular VHL disease, and to establish genotype-phenotype correlations between genotype category and visual function.MethodsCross-sectional and molecular genetic study. Of 890 patients with VHL disease, 335 had ocular involvement in the form of RCHs. Statistical analysis was used to correlate the structure of the mutated VHL protein with the ocular phenotype.ResultsThree genotype categories (amino acid substitutions, protein-truncating mutations, and complete deletions of VHL protein) were defined in all patients. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations compared with those with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity compared with the other 2 genotype categories.ConclusionPatients with complete deletions of VHL protein have the lowest prevalence of ocular disease and the most favorable visual outcome.Clinical relevanceThe VHL mutation genotype may be used to predict the prevalence and outcome of ocular VHL disease and to guide ophthalmic follow-up.
| S-EPMC3019103 | biostudies-literature
Project description:This scientific report aims to investigate the genotype-phenotype correlations of retinal hemangioblastoma (RH) in von Hippel-Lindau (VHL) disease. The study included 77 patients with genetically confirmed VHL disease who visited an ophthalmology clinic for the evaluation of RH. The presence, location, and size of RH were evaluated, Patients were categorized into three groups based on variants: HIF-1α binding site missense (HM), non-HIF-1α binding site missense (nHM), and truncating (TR) mutations. Fifty-six patients (72.7%) had RH in either eye, and 24 had bilateral RH. Sixteen patients (20.8%) had juxtapapillary RH in either eye. Nine patients had RH ≥ 2.0 disc diameters in size. VHL c.208G>A variant was the most frequent single mutation. Compared with patients having nHM mutations (15 patients) in VHL gene, patients with HM mutations (33 patients) or TR mutations (26 patients) presented a greater number of eyes affected (p = 0.007 and 0.004, respectively), a greater number of RH (p = 0.012 and 0.003, respectively), and more frequent presentation of large RH ≥ 2.0 disc diameters (p = 0.012, and 0.013, respectively). In conclusion, this study provides a deeper understanding of the genetic spectrum of VHL disease in Korean VHL disease and highlights the importance of the location of missense mutations regarding the risk of RH.
| S-EPMC11458008 | biostudies-literature
Project description: Not available
| S-EPMC3953906 | biostudies-literature
Project description:The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of a ubiquitin ligase complex containing elongin B, elongin C, cullin 2, and Rbx1, which acts as a negative regulator of hypoxia inducible factor (HIF). VHL ubiquitinates and degrades the alpha subunits of HIF, and this is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in the maintenance of primary cilium, extracellular matrix formation, and tumor suppression. We undertook a series of proteomic analyses to gain a comprehensive picture of the VHL-interacting proteins. We found that the ARF tumor suppressor interacts with VHL30, a longer VHL isoform, but not with VHL19, a shorter VHL isoform. ARF was found to release VHL30 from the E3 ligase complex, promoting the binding of VHL30 to a protein arginine methyltransferase, PRMT3. Our analysis of the VHL19 interactome also uncovered that VHL19 displays an affinity to collagens and their biosynthesis enzymes.
| S-EPMC3208728 | biostudies-literature