Germline Von Hippel-Lindau Mutations Research Articles

A nonsense mutation in VHL causing Von Hippel-Lindau syndrome in a large Chinese family—a genetic study of familial neoplastic disease

Von Hippel-Lindau (VHL) syndrome is a multi-organ neoplastic disease characterized by highly vascular and cystic tumors in the central nervous system (CNS), retina, and visceral lesions, which are mainly caused by germline mutations in VHL. We aimed to detect novel mutations in VHL gene in families with VHL. Here, a large consanguineous four-generation family with variant phenotypes of VHL syndrome was recruited, and its molecular genetics were tested via Sanger sequencing. And various tools and databases were used to predict the variant pathogenicity, frequency, and protein function. Genetic investigation detected a c.351G > A nonsense mutation in VHL that altered the downstream reading frame and created a premature TGA stop signal, resulting in severely truncated pVHL (p.Trp117Ter). This mutation is absent from most public databases, and functional prediction bioinformatic tools demonstrated that this residue is conserved and that this variant is highly likely to be deleterious. The c.315G > A nonsense mutation in VHL is the causal mutation of this kindred that may lead to clear familial aggregation of VHL syndrome because of the dysfunction of the truncated pVHL.

Belzutifan treatment of Von Hippel-Lindau (VHL) related central nervous system (CNS) hemangioblastomas (HBs): A single institution experience.

2078 Background: Patients with inactivating germline mutations in the VHL gene develop CNS (brain and/or spine) HBs and/or renal cancers, pheochromocytomas and pancreatic neuroendocrine tumors. The oral HIF2a inhibitor belzutifan has been approved by FDA for the treatment of VHL-related HBs. We present here data on a cohort of VHL patients with CNS HBs treated with belzutifan in a single institution. Methods: Adult VHL patients, with radiologically documented CNS (brain and/or spine) HBs that displayed documented growth within the last 6 months prior to therapy, were treated with an initial dose of 120 mg belzutifan orally per day. Target lesions included HBs > 0.4cm long in one maximal cross-sectional diameter. Lesions were imaged by MRI at 1.5, 3, 6 months after initiation of treatment and at 6-month intervals thereafter. Solid enhancing lesions, associated cysts and peritumoral edema were recorded and quantified. Tumor sizes were evaluated by RECIST 1.1 criteria and volumetric analysis. All patients were evaluated and treated in the Hemangioblastoma Center and the VHL Clinic of the Massachusetts General Hospital Cancer Center. Results: At the time of analysis, 9 females and ten 10 male VHL patients (n=19) have been treated. Median age at treatment initiation was 36 yo (range 19-59). Median follow up is 12 months (range 1-19.5 months). Two patients were not yet evaluable for response. Of 17 evaluable patients, 8 had a PR (ORR 47%; 95% CI, 34-60), 8 had SD and 1 patient had progression (PD, 5.8%). Two patients had dose reduction to 80 mg/d because of anemia. No patient had grade 3 or greater toxicity and no patient experienced a CNS related toxicity during treatment. Volumetric analysis of solid and cystic components of the lesions, VHL germline mutations and other correlates of response to belzutifan will be presented. Conclusions: Real world data collected at a single institution confirm the high response rate of both solid and cystic components of CNS HBs to the FDA approved HIF2a inhibitor, belzutifan. Belzutifan was well tolerated. Further prospective controlled studies addressing the optimal dose, schedule and duration of treatment of HBs with belzutifan are required.

NIMG-110. FIRST CLINICAL EXPERIENCE WITH BELZUTIFAN IN VON HIPPEL-LINDAU DISEASE-ASSOCIATED CNS HEMANGIOBLASTOMA

Abstract The authors present two cases of von Hippel-Lindau (VHL) disease-associated hemangioblastomas in the central nervous system (CNS) treated with the newly-approved HIF-2α inhibitor, belzutifan. The first case is that of a 31-year-old female with confirmed pathogenic germline VHL mutation who presented with multiple hemangioblastomas diagnosed at 25 years of age. The patient was first managed surgically with resection of three posterior fossa hemangioblastomas but re-presented five years later with headaches and paresthesias of the fingers. She was found to have interval progression of an intramedullary cervical lesion that was monitored radiographically, as well as a new cerebellar lesion. A cerebellar lesion was resected, but the cervical hemangioblastoma was not. Four months after surgery, the patient was started on belzutifan, which she tolerated without issue, and a brisk reduction in peri-lesional edema was observed in the cervical spine and remaining intracranial foci after 2 months of treatment. The second patient is a 30-year-old male with familial VHL disease, initially diagnosed after the discovery of a retinal hemangioblastoma at age 10. He was found to have multiple cerebellar hemangioblastomas, treated with resection at age 24 and then with stereotactic radiosurgery (SRS) at age 25, complicated by radiation necrosis. Imaging surveillance revealed disease progression at age 29 for which he was started on belzutifan. Follow-up imaging after three one month cycles revealed a reduction in perilesional edema and reduced lesion mass effect. Both patients tolerated belzutifan well, with only anemia and fatigue. We highlight in this report our initial experience and early imaging findings associated with belzutifan used for VHL disease-associated CNS hemangioblastomas.

First clinical experience with belzutifan in von Hippel-Lindau diseaseassociated CNS hemangioblastoma.

We present two cases of von Hippel–Lindau (VHL) disease-associated hemangioblastomas in the CNS treated with the newly approved HIF-2α inhibitor, belzutifan. The first case is a 31-year-old female with confirmed pathogenic germline VHL mutation who presented with multiple hemangioblastomas. The patient was started on belzutifan, and a brisk reduction in perilesional edema was observed after 2 months of treatment. The second patient is a 30-year-old male with familial VHL disease. Imaging revealed multiple cerebellar hemangioblastomas, and follow-up imaging after three cycles of belzutifan revealed a reduction in perilesional edema. Both patients tolerated belzutifan well, with only anemia and fatigue. We highlight our initial experience and early imaging findings associated with belzutifan in VHL disease-associated CNS hemangioblastomas.

Long term outcomes for patients with von Hippel-Lindau and Pheochromocytoma: defining the role of active surveillance

IntroductionPatients with a confirmed germline mutation in the von Hippel-Lindau (VHL) tumor suppressor gene have been followed at the National Cancer Institute since the 1980s. In this study, we identify VHL patients with pheochromocytoma and long-term follow-up to determine the best candidates for active surveillance and surgical resection. MethodsA prospectively collected database of patients with a confirmed germline VHL mutation was reviewed to identify patients with a history of pheochromocytoma and at least 10 years of follow up. The presence of symptoms was assessed at the time of resection. Imaging data obtained at each clinic visit was reviewed to evaluate mass size and annual growth rate. Catecholamine data were reviewed to evaluate for data above the upper limit of the reference range. Masses that underwent imaging at least 3 months apart were considered in our surveillance cohort. ResultsMedian follow up was 16.7 years. There was a size-dependent increase in catecholamine production (P<0.05). For 36 masses on active surveillance, growth rate increased exponentially from 0.03 cm/y when masses were <1 cm to 0.32 cm/y when masses were greater than 2 cm. Approximately 1/3 of patients developed another pheochromocytoma after initial resection with a median time of 7.9 years. Partial adrenalectomy was associated with no metastatic events and a steroid-free rate of 97%. ConclusionActive surveillance is a safe strategy for management of VHL associated pheochromocytoma in masses less than 2 cm.

Abstract 1311: Inter- and intra-tumor heterogeneity of genetic and immune profiles in hereditary clear cell renal cell carcinoma

Abstract [Background] Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome attributed to germline VHL mutation. Patients with this disease are at risk of developing multiple independent clear cell renal carcinomas (ccRCCs), which offers a unique opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles in the same patient. [Method] We selected seven patients with clinically diagnosed VHL disease who underwent one or two surgeries, in each of which two to five ccRCC tumors (total, n = 25) were removed. We harvested one to six regions from each tumor (total, n = 48), and performed whole-exome sequencing on them, together with normal blood (n = 7), cyst (n = 3), and adjacent normal renal tissue (n = 7) specimens from these patients. In addition, we carried out RNA-sequencing (for 20 tumors and 3 adjacent tissues) and digital multiplexed gene expression analysis using the NanoString nCounter system with Human Immunology V2 panel (for 36 tumors and 5 adjacent tissues) to clarify their immune profiles. [Result] Germline VHL mutations were confirmed in all seven patients. A total of 1,141 non-silent somatic mutations (8-44 mutations per patient) were detected, including 22 mutations affecting previously reported driver genes (such as BAP1, PBRM1, PTEN, PIK3CA, and SETD2). In consistent with previous reports, tumors arising in this context are clonally independent and harbor distinct secondary events, including mutations and copy number alterations (as exemplified by loss of heterozygosity of 3p). By contrast, multiple specimens from the same tumor showed almost the same genetic alterations, although several subclonal mutations were observed. Unsupervised hierarchical clustering of gene expression data discovered two robust subsets with distinct immune-related signatures. Particularly, the subset with high immune signature (n = 29) showed increased antigen presentation machinery genes (B2M, TAP1 and TAP2) and cytotoxic T lymphocyte genes (CD8, PRF1, and GZMA) than that with low immune signature (n = 19), suggesting a higher cytolytic activity in the former subset. Pathway analysis revealed the enrichment of cytokine interaction, JAK-STAT signaling and Toll-like receptor signaling. Interestingly, specimens from the same tumor invariably showed a similar immune signature, whereas different tumors frequently exhibit different immune signatures despite the identical immune background, suggesting a greater difference of immune status across tumors than within a tumor. [Conclusion] This study delineates inter- and intra-tumor heterogeneity of genetic and immune profiles in hereditary clear cell renal cell carcinoma. Our findings demonstrate more profound inter-tumor than intra-tumor heterogeneity in immune status, suggesting that tumor factors have a greater impact on immune microenvironment than host factors. Citation Format: Mariko Tabata, Yusuke Sato, Yasunori Kogure, Marni B. McClure, Yuji Kumade, Yuki Saito, Sumito Shingaki, Kota Yoshifuji, Junji Koya, Kazushi Yoshida, Takashi Kohno, Kenichi Chiba, Ai Okada, Yuichi Shiraishi, Haruki Kume, Keisuke Kataoka. Inter- and intra-tumor heterogeneity of genetic and immune profiles in hereditary clear cell renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1311.

Retinal haemangioblastomas in von Hippel-Lindau germline mutation carriers: progression, complications and treatment outcome.

PurposeEvaluation of phenotype and treatment outcome of retinal haemangioblastomas (RH) in von Hippel–Lindau (VHL) disease and correlation of these features with the genotype of VHL germline mutation carriers.MethodsRetrospective analysis of a longitudinal cohort of 21 VHL germline mutation carriers and RH. Clinical and genetic data were obtained to analyse the correlation of genotype with phenotype and treatment outcomes.ResultsAll patients were categorized in two genotypic categories: missense mutations (MM) and truncating mutations (TM). Mean follow‐up duration was 16.3 years and did not differ significantly between mutation groups (p = 0.383). Missense mutations (MM) carriers (n = 6) developed more progression‐related complications compared to TM carriers (n = 15) (p = 0.046). Vitreoretinal surgery was more often applied in MM carriers (p = 0.036). Moderate (visual acuity (VA)20/80 to 20/200) to severe (VA < 20/200) visual impairment was observed in 53.3% of the eyes of MM carriers and 28.1% of the eyes of TM carriers at last recorded visit.ConclusionMissense mutations in VHL patients seem to have a higher prevalence of progression‐related complications. Missense mutations (MM) carriers required therefore more often vitreoretinal surgical treatment with a worse treatment outcome. Genetic analysis may play a role in determining a pro‐active treatment strategy and prognosis for RH.

An Autopsy Case Report of Von Hippel-Lindau Syndrome-Type 2C Masquerading as Pre-eclampsia and Resulting in Maternal and Foetal Mortality

A 23-year-old female with seven months pregnancy, presented with gestational hypertension associated with mild proteinuria and was diagnosed clinically as pre-eclampsia and referred to tertiary care centre. She also had progressive breathlessness and giddiness. On examination, pallor, Blood pressure (BP) of 180/100 mm Hg and crepitations in left lower lung were noted. Laboratory investigations revealed neutrophilic leucocytosis and a profile of Disseminated Intravascular Coagulation (DIC). An ultrasound (USG) of the abdomen showed a gravid uterus with Intrauterine Foetal Death (IUFD) and a left adrenal mass. The clinical diagnosis was acute hypertensive heart failure with severe pre-eclampsia. She was put on three anti-hypertensives and ventilatory support, but she succumbed to her illness, within three days of admission. A complete autopsy was performed. The autopsy revealed hypertensive heart disease with marked left ventricular hypertrophy, severe coronary atherosclerosis, cystic bilateral adrenal pheochromocytoma, a cystic para-aortic paraganglioma, a pancreatic Neuroendocrine Tumour (NET) with lymph node metastasis. Hence, a diagnosis of DIC with refractory hypertension in Type 2C Von Hippel-Lindau (VHL) syndrome was established. VHL syndrome is an autosomal dominant disorder caused by germline VHL mutation which leads to development of various tumours. VHL disease is classified into four subtypes and VHL type 2C has predominantly pheochromocytomas without haemangioblastoma and Renal Cell Carcinoma (RCC). As the patient mimicked pre-eclampsia clinically, the diagnosis of VHL was missed. Bilateral adrenal cystic masses with gestational hypertension should be thoroughly evaluated, at the earliest, for familial pheochromocytomas or VHL syndromes as they may prove fatal.

Retinal hemangioblastomas in Von Hippel‐Lindau germline mutation carriers: progression, complications and treatment outcome

AbstractPurposeEvaluating the phenotype, complications and treatment outcome of retinal hemangioblastomas (RH) and correlating this features with the genotype of Von Hippel‐Lindau (VHL) germline mutation carriers.MethodsRetrospective analysis of the medical and genetic records of 21 individuals with a VHL germline mutation and a diagnosis of RH. Germline mutation status was correlated to phenotype, complications, treatment methods and outcomes. Mutations were categorized in two genotypic categories: the truncating mutation (TM) group and the missense mutation (MM) group.ResultsFrom the 36 VHL germline mutation carriers, 21 VHL patients developed RH. Prevalence of RH in VHL disease was higher in TM carriers (15 of 21, 68.2%) vs. 40% of the MM carriers (6 of 15). The mean age of diagnosis of RH was 25.7 years. There was no significant difference in age of diagnosis of RH between genotypic categories (P = 0.931). Mean follow‐up duration was 16.3 years and did not differ significantly between the mutation groups (P = 0.383). Bilateral involvement was observed in 66.7% of the patients. Missense mutation (MM) carriers (n = 6) developed more RH (more than 5 RH: 50.0% vs. 38.5%), had a larger extent of peripheral retinal involvement of ocular VHL disease (66.7% vs. 35.7% all quadrants involved) and developed more progression‐related complications compared to TM carriers (n = 15) (100% vs. 46.7%). Complete tumor regression at last recorded visit was achieved in fifteen patients (71.4%). Moderate (VA 20/80 to 20/200) to severe (less than VA 20/200) visual impairment was observed in 53.3% of the eyes of MM carriers and 28.1% of the eyes of TM carriers at last recorded visit.ConclusionsGermline mutation status might play a role in the course of progression of RH in VHL disease. In our observational study, VHL missense mutation carriers had a more complicated progression of RH than carriers of a truncating mutation.

GENE-62. IDENTIFICATION OF FGFR4 p.G388R VARIANT IN CEREBELLAR HEMANGIOBLASTOMAS

Abstract BACKGROUND While most hemangioblastomas (~70%) are sporadic and occur predominantly in the cerebellum, they may present as well as familial form associated with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder caused by germline mutations of the VHL gene that trigger nuclear translocation of hypoxia-inducible factor (HIF)-1α and angiogenesis. Although inactivation of VHL, a tumor suppressor gene, has been observed in hemangioblastomas, the underlying pathogenic mechanisms responsible for familial and sporadic hemangioblastomas remain incompletely understood. METHODS Whole exome sequencing of cerebellar hemangioblastoma tumors and matched blood leukocytes from 24 patients, age 24–63, was performed. After preparation and amplification of barcoded libraries, exomes were captured using Kapa Biosystems methodology and paired-end sequenced on Illumina HiSeq 2500 to an average 100-fold coverage. Following read alignment to hg19 genome, tumor and germline (leukocyte) sequences were compared, and pathogenic single nucleotide variants (SNVs) identified and validated by re-sequencing followed by pathway analysis. Additionally, tumor RNA isolated using Maxwell Promega was sequenced on Illumina instrument and the expression counts determined and normalized. RESULTS We found 314 pathogenic and/or highly deleterious mutations (both germline and somatic) with a median of 13 mutations per patient. Five patients had VHL syndrome (germline VHL mutation) and 4 carried somatic VHL mutations. Among the VHL tumors, 82 mutations were identified, including HNF1B, NOTCH1 and TCF7L1, suggesting a potential contribution of altered RNA metabolism based upon pathway analysis. Among all hemangioblastomas, germline growth factor receptor variants (FGFR4 p.G388R (14/23 (61%) patients), IGF1R, PDGFRA and TYK2) known to activate STAT3 signaling and induce HIF-1α and angiogenesis, were identified. Non-hierarchical clustering of RNA sequencing data revealed two transcriptionally-distinct subtypes of hemangioblastomas. CONCLUSIONS Our findings indicate that hemangioblastomas can also occur by germline mutations known to activate STAT3 signaling, which may have significant implication in genetic testing and counseling of patients with hemangioblastomas.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel-Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.

MOLECULAR EPIDEMIOLOGY OF RENAL CANCER

Kidney cancer consists of renal cell cancer (RCC) accounting for over 90 % of all kidney carcinomas and the transitional cell cancer. Clear cell cancer is a predominant type (80–85 %) of RCC. Smoking, overweight, obesity, hypertension, occupational exposures to pesticides, specifically to trichloroethylene are considered causal risk factors for sporadic i.e. non-hereditary RCC. The majority of sporadic RCC have polygenic etiology. They develop as a result of combined effect of large number of low penetrance genetic susceptibility genes (genetic polymorphism). The interplay of exposures to environmental risk factors and genetic susceptibility of exposed individuals is believed to influence the risk of developing sporadic RCC. Inheritance of high penetrance genes is associated with very high risk of the RCC. To these genes belongs, for example, VHL (von Hippel–Lindau). Germline mutations in VHL are causing VHL syndrome and hereditary type of RCC. Risk of RCC in individuals with germ-line mutations is very high however the proportion RCC associated with these events is very low (&gt;5–7 %). Environmental factors virtually do not influence the risk of these cancers.The studies in molecular epidemiology based on candidate gene approach have shown that certain types (variants) of polymorphisms of GST, MTHFR, TYMS, VHL genes are associated with RCC. The genome wide association studies identified over twenty locus with single nucleotide polymorphism affecting the risk of RCC. The risk loci so far identified for RCC account for only about 10 % of the familial risk of RCC. Thus more studies with larger sample size are needed. As more RCC susceptibility alleles are discovered, deciphering the biological basis of risk variants should provide new insights into the biology of RCC that may lead to new approaches to prevention, early detection and therapeutic intervention.

Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas.

Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS) tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL) syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.

Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel-Lindau (VHL), Succinate Dehydrogenase (SDHX) and Transmembrane Protein 127 (TMEM127).

Alterations of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX), and TMEM127 have been associated with the development of pheochromocytomas (PCs) and paragangliomas (PGLs) and are also associated with the development of renal neoplasms. This study involved 2 primary renal PGL and 12 cases of PC/PGL with associated renal neoplasia with a mean follow up of 74months. Germline VHL and SDHX mutation status was obtained from the medical record. Immunohistochemistry for SDHB and mutation analysis for TMEM127 was performed, in addition to analysis of The Cancer Genome Atlas datasets for SDHX and TMEM127 mutated renal cell carcinomas (RCCs). The spectrum of renal neoplasia included clear cell and tubulocystic and papillary RCC, as well as a case of multiple papillary adenomas. Three patients had metastatic PC/PGL and three patients had VHL syndrome. Previously unreported TMEM127 alterations were identified in two patients, both without evidence of VHL syndrome or SDH-deficiency, and were classified as variants of uncertain significance. Primary renal PGL and neoplasia was associated with about 2% of 710 cases of PC/PGL. These were diagnosed concurrently or on average 27months prior to the PC/PGL, and most were low-grade, low-stage clear cell RCCs. Up to half of patients with PC/PGL and renal neoplasia had VHL syndrome, SDH deficiency, or alterations in TMEM127. One (of three) case of metastatic PC/PGL had SDHB mutation and loss of SDHB by immunohistochemistry. The other two cases had retained SDHB expression.

Von Hippel-Lindau disease: a single gene, several hereditary tumors.

The Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the predisposition for multiple tumors caused by germline mutations in the tumor suppressor gene VHL. This disease is associated with a high morbidity and mortality and presents a variable expression, with different phenotypes from family to family, affecting different organs during the lifetime. The main manifestations of VHL are hemangioblastomas of the central nervous system and retina, renal carcinomas and cysts, bilateral pheochromocytomas, cystic and solid tumors of the pancreas, cystadenomas of the epididymis, and endolymphatic sac tumors. The discovery of any of the syndrome components should raise suspicion of this disease and other stigmas must then be investigated. Due to the complexities associated with management of the various VHL manifestation, the diagnosis and the follow-up of this syndrome is a challenge in the clinical practice and a multidisciplinary approach is needed. The particular relevance to endocrinologists is the detection of pheochromocytomas in 35% and islet cell tumors in 17% of VHL patients, which can be associated with hypertension, hypoglycemia, cardiac arrhythmias, and carcinoid syndrome. The purpose of this review is to define the Von Hippel-Lindau syndrome addressing its clinical aspects and classification, the importance of genetic counseling and to propose a protocol for clinical follow-up.

Difference in CXCR4 expression between sporadic and VHL-related hemangioblastoma.

Central nervous system hemangioblastomas occur sporadically and in patients with von Hippel–Lindau (VHL) disease due to a VHL germline mutation. This mutation leads to enhanced transcription of chemokine receptor 4 (CXCR4), its ligand (CXCL12) and vascular endothelial growth factor A (VEGFA). We aimed to determine in VHL-related and sporadic hemangioblastomas CXCR4, CXCL12, and VEGFA protein expression and to correlate this to hemangioblastoma size and expression in normal surrounding tissue. 27 patients with a hemangioblastoma were included for analysis of immunohistochemistry of tissue, MRI and DNA. Hemangioblastomas overexpress CXCR4, CXCL12, and VEGFA compared to normal surrounding tissue. In sporadic hemangioblastomas the mean percentage of CXCR4 positive hemangioblastoma cells was 16 %, SD 8.4, in VHL-related hemangioblastomas 8 %, SD 4.4 (P = 0.002). There was no relation between preoperative tumor size and CXCR4 or CXCL12 expression. Compared to normal surrounding tissue CXCR4, CXCL12, and VEGFA were overexpressed in hemangioblastomas. Most interestingly, sporadic hemangioblastomas overexpress CXCR4 compared to VHL-related hemangioblastoma.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-016-9879-3) contains supplementary material, which is available to authorized users.

Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016.

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an inherited tumor syndrome caused by germline mutations in the VHL tumor suppressor gene. It is characterized by hemangioblastoma in the central nervous system and retina, renal cell carcinoma, pancreatic tumor and cysts, and pheochromocytoma. In this study, we detected 26 germline mutations in the VHL gene of Korean patients, of which 1 was a novel mutation, c.417_418insT. We also integrated our data from this study with the published literature to identify 55 VHL germline mutations in Koreans, and identified a unique hotspot at codon 70. Nine unrelated patients (9/55, 16.4%) had the same amino-acid substitution at codon 70 (Glu70Lys) and showed VHL type 1 phenotypes. Although this mutation was shown to have a mild effect on VHL function, four of the nine patients (44.4%) subsequently developed multiple central nervous system hemangioblastomas or retinal hemangioblastoma. However, this hotspot has not been identified in Chinese or Japanese patients. This study provides information on the spectrum of VHL mutations in Korean VHL disease and contributes to a better understanding of VHL disease in terms of improvements in the clinical management of VHL families.

New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation

The von Hippel-Lindau gene (VHL), composed of three exons, encodes a protein, pVHL, with diverse tumor suppressor activities. Germline VHL mutations are found in patients with von HippelLindau (VHL), an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of highly vascularized benign and malignant tumors including central nervous system hemangioblastomas, retinal hemangiomas, clear cell renal carcinomas (ccRCCs), pheochromocytomas, and pancreatic neuroendocrine tumors (1). Biallelic inactivation of VHL, whether via mutation or promoter methylation, is found in VHL-associated tumors and in nearly 90% of sporadic ccRCC tumors (2,3), the most common form of sporadic kidney cancer. Among its activities, pVHL functions as the substrate recognition module of a multiprotein ubiquitin ligase complex, and, by recruiting hypoxia-inducible factor (HIF) 1α and 2α to this complex, mediates their oxygen-dependent degradation (4). VHL mutations that interfere with HIF-α recognition promote aerobic glycolysis and support neoangiogenesis, perhaps the most intensively studied consequences of pVHL loss. However, regulation of HIF-α expression is unlikely to be the sole mechanism underlying the tumor suppressor function of pVHL. Given its role as the substrate recognition module of a multiprotein complex, it is reasonable to assume that pVHL has additional activities that depend on protein–protein interactions unrelated to (or perhaps complementary with) HIF stabilization, and that deregulation of one or more of these activities contributes to tumor formation, likely in a tissue-specific manner. Indeed, pVHL has been implicated in a number of cellular processes that appear to be HIF independent, including cell cycle regulation, extracellular matrix assembly, and cytoskeleton stability (5). The development of ccRCC is associated with both genetic (eg, VHL germline mutation) and environmental factors, particularly long-term exposure to the industrial solvent trichloroethylene (TCE). Although TCE exposure does not affect the histopathology of sporadic ccRCC, its onset is earlier in TCE-exposed individuals, and the VHL gene in a substantial percentage of these tumors contains a specific mutation of a cytosine to thymidine at nucleo

Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients

Biallelic mutations of the von Hippel-Lindau (VHL) gene are the most common cause of sporadic and inherited renal cell carcinoma (RCC). Loss of VHL has been reported to affect cell proliferation by deregulating cell cycle-associated proteins. We report that the VHL gene product (pVHL) inhibits E2F1 expression at both mRNA and protein level in zebrafish and human RCC cells, while loss of VHL increases E2F1 expression in patient kidney tumour tissue and RCC cells, resulting in a delay of cell cycle progression. RCCs from von Hippel-Lindau patients with known germline VHL mutations express significantly more E2F1 compared to sporadic RCCs with either clear-cell (cc) or non-cc histology. Analysis of 138 primary RCCs reveals that E2F1 expression is significantly higher in tumours with a diameter ≤7 cm and with a favourable American Joint Committee on Cancer (AJCC) stage. The expression of E2F1 in RCC significantly correlates with p27 expression, suggesting that increased expression of E2F1 in RCC induces tumour cell senescence via p27. Cox regression analysis shows significant prediction of E2F1 expression for disease-free survival and overall survival, implying that E2F1 expression in kidney tumour is a novel prognostic factor for patients with RCC.