Genetic causes of erythrocytosis and the oxygen-sensing pathway

Idiopathic erythrocytosis is an uncommon disease, and is defined by an increase in red blood cell mass. The differential diagnosis of erythrocytosis is extensive, and can be divided into primary and secondary forms. Primary erythrocytoses are due to intrinsic defects in erythroid precursor cells and are characterized by low erythropoietin levels. Secondary erythrocytoses are extrinsic to erythroid progenitors and are characterized by either high or inappropriately normal erythropoietin levels. A distinct subset of secondary erythrocytoses are due to genetic mutations in key proteins of the oxygen-sensing pathway. These proteins constitute the core molecular machinery of oxygen-sensing with respect to red blood cell control. Apart from assigning physiologic roles for these proteins, studies of these rare mutations have (i) revealed the exquisite sensitivity of this pathway to genetic perturbations, (ii) highlighted important functional regions of the proteins, and (iii) provided a basis for potentially targeting this pathway for therapeutic benefit.     

Distinct von Hippel-Lindau gene and hypoxia-regulated alterations in gene and protein expression patterns of renal cell carcinoma and their effects on metabolism

During the last decade the knowledge about the molecular mechanisms of the cellular adaption to hypoxia and the function of the “von Hippel Lindau” (VHL) protein in renal cell carcinoma (RCC) has increased, but there exists little information about the overlap and differences in gene/protein expression of both processes. Therefore the aim of this study was to dissect VHL- and hypoxia-regulated alterations in the metabolism of human RCC using ome-based strategies. The effect of the VHL- and hypoxia-regulated altered gene/protein expression pattern on the cellular metabolism was analyzed by determination of glucose uptake, lactate secretion, extracellular pH, lactate dehydrogenase activity, amino acid content and ATP levels. By employing VHL⁻/VHL⁺ RCC cells cultured under normoxic and hypoxic conditions, VHL-dependent, HIF-dependent as well as VHL-/HIF-independent alterations in the gene and protein expression patterns were identified and further validated in other RCC cell lines. The genes/proteins differentially expressed under these distinct conditions were mainly involved in the cellular metabolism, which was accompanied by an altered metabolism as well as changes in the abundance of amino acids in VHL-deficient cells. In conclusion, the study reveals similarities, but also differences in the genes and proteins controlled by VHL functionality and hypoxia thereby demonstrating differences in the metabolic switch of RCC under these conditions.     

Bilateral Peripapillary Exophytic Retinal Hemangioblastomas

A 14-year-old Iranian girl was referred for evaluation of bilateral elevation of the peripapillary retina. Fluorescein angiography was consistent with bilateral peripapillary exophytic retinal hemangioblastomas as seen in angiomatosis retinae (von Hippel’s disease). Argon laser photocoagulation of the more severely affected left eye was performed with minimal effect upon the tumor.     

Origin of Endolymphatic Sac Tumor

Autopsy temporal bone sections showing a one mm papillary glandular neoplasm, confined to the left endolymphatic duct, are described. This is the second literature report confirming the post-mortem site of origin of the “endolymphatic sac tumor”. The patient died after surgery for right vestibular schwannoma, but no features of von Hippel Lindau disease or neurofibromatosis 2 had been displayed clinically or at autopsy. A study of the epithelium of normal human mature endolymphatic ducts and sacs (EDSs) in archival temporal bone sections showed hyperplastic tubular outgrowths, usually situated in the intraosseous portion of the endolymphatic sac, in most cases. Such appearances imply that the epithelium of the EDS has the potential of producing a malignant papillary glandular neoplasm. Papillary ingrowths, some forming collagenous polypoid projections, and cysts were frequent among the epithelial cells. Psammoma bodies were present in the ducts and sacs of older patients. Appearances suggesting erosion of the bony interface of vestibular aqueduct with EDS could be ascribed to the entry and exit of blood vessels into and from the vestibular aqueduct. Care should be taken in the evaluation of surgical or autopsy material from EDSs not to overcall any of these normal features as malignant.     

Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Von Hippel–Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 + 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.     

Hemangioblastoma of the corpus callosum: A case report and review of the literature on its origin

A third case of corpus callosum hemangioblastoma (HB) is presented. With no preoperative embolization, surgery was uneventful and the postoperative course was excellent. Based on the literature, we attempted to clarify the histogenesis of HB and to explain why they are exceptional in the supratentorial region in contrast to the posterior cranial fossa. The VHL gene is expressed particularly in Purkinje cells of the cerebellum, but this expression is also possible in supratentorial structures. Its mutation leads to developmental arrest of angioblasts that become potentially neoplastic cells. These CD133-positive pluripotent neoplastic angioblasts, similar to stem cells, may be immature HB in the brain. They also express VEGF, coexpress Epo/EpoR, and are capable of differentiation into primitive vascular structures. This coexpression may not only mediate developmental stagnation, but may also induce HB proliferation. Therefore, HB tumorigenesis may be initiated during embryogenesis and may originate from angiomesenchyma because of the expression of three cell types (stromal cells, pericytes, and endothelial cells) in vimentin. Their capacity for proliferation and differentiation in HB depends on the microenvironment.     

Molecular genetic analysis of the von Hippel-Lindau and human peroxisome proliferator-activated receptor gamma tumor-suppressor genes in adenocarcinomas of the gastroesophageal junction.

We investigated whether 2 candidate tumor-suppressor genes, VHL at 3p25-26 and PPAR gamma at 3p24.2-25, are involved in GEJ adenocarcinogenesis. In 43 GEJ tumor samples from 40 patients, the entire coding sequence of the VHL gene and the 5' and part of the 3' UTR as well as exons 3 and 5 of the PPAR gamma gene were screened by PCR-SSCP analysis. LOH at 3p25-26 was analyzed with 2 polymorphic microsatellite markers and with the VHL exon 1 and intron 2 polymorphisms. The relationship between LOH and clinicopathologic parameters was assessed. Expression of VHL was investigated by immunohistochemistry with a VHL-specific antibody. PCR-SSCP analysis of VHL revealed 2 different aberrant patterns in 19 patients. Upon DNA sequencing, 1 pattern appeared to be a previously described exon 1 polymorphism. The other single aberrant pattern was an intron 2 polymorphism, not yet described. PCR-SSCP analysis of PPAR gamma showed no aberrant migration patterns. LOH analysis revealed 3p25-26 loss in 24/36 (67%) informative cases, but this was not significantly correlated with clinicopathologic parameters. By immunohistochemistry, all tumors showed expression of VHL protein. Despite the very frequent LOH of 3p in GEJ adenocarcinomas, mutations in VHL and PPAR gamma were not detected. Mutations outside the screened sequences, a gene dosage effect or involvement of another tumor-suppressor gene on 3p as the target of LOH should be considered.