Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma

Renal cell carcinoma is unique among the genitourinary malignancies in that close to one third of affected patients show signs and symptoms of a paraneoplastic syndrome. The paraneoplastic syndromes associated with renal cell carcinoma range from those manifesting in constitutional symptoms (ie, fever, cachexia, and weight loss) to those that result in specific metabolic and biochemical abnormalities (ie, hypercalcemia, nonmetastatic hepatic dysfunction, amyloidosis, etc). The presence of a paraneoplastic syndrome in a patient with renal cell carcinoma is neither a marker of metastatic disease nor necessarily indicative of a poor prognosis. The importance of understanding the pathophysiology and biology behind the many paraneoplastic syndromes associated with renal cell carcinoma lies in the fact that the presence of these protean symptoms may be the initial presentation of either primary or recurrent disease. In this review, we will describe the proposed mechanisms of action of the many paraneoplastic syndromes associated with renal cell carcinoma as well as outline the clinical evaluation and treatment options currently available for these noteworthy disorders.     

Von Hippel-Lindau disease

Germline mutations in the VHL tumour suppressor gene may cause a variety of phenotypes including von Hippel-Lindau (VHL) disease, familial phaeochromocytoma and inherited polycythaemia. VHL disease is a multisystem familial cancer syndrome and is the commonest cause of familial renal cell carcinoma (RCC). VHL disease provides a paradigm for illustrating how studies of a rare familial cancer syndrome can produce advances in clinical medicin and important insights into basic biological processes. Thus the identification of the VHL gene has improved the diagnosis and clinical management of VHL disease and provided insights into the pathogenesis of sporadic clear cell RCC. Functional investigations of the VHL gene product have provided novel information on how cells sense oxygen and the role of hypoxia-response pathways in human tumourigenesis. Such information offers prospects of novel therapeutic interventions for VHL disease and common cancers including RCC.     

Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease

Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor, cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma. Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20-30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic Janus mutation at Cys620 of RET. In Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.     

Familial non-syndromic clear cell renal cell carcinoma

The diagnosis of familial non-syndromic clear cell renal cell carcinoma is one of exclusion. In families presenting with clear cell RCC a germline VHL mutation and a constitutional translocation of chromosome 3 must be excluded before familial non-syndromic clear cell RCC can be diagnosed. Large familial non-syndromic clear cell RCC kindreds are uncommon and a predisposing gene has not been identified. However inheritance is autosomal dominant in most cases and age at onset is earlier than in sporadic cases. Recognition and appropriate screening of familial non-syndromic clear cell RCC cases will reduce morbidity and mortality. Large scale collaborative linkage studies may provide a basis for the identification of familial non-syndromic clear cell RCC susceptibility gene(s).     

VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma

Loss of von Hippel-Lindau tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma, resulting in the aberrant expression of genes that control cell proliferation, metabolism, invasion and angiogenesis. The molecular mechanisms by which loss of function leads to tumorigenesis are not yet fully defined. The von Hippel-Lindau gene product is part of an ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteasomal degradation, linking hypoxia response genes to renal cell carcinoma oncogenesis. Loss von Hippel-Lindau gene function also promotes cell invasiveness in response to hepatocyte growth factor, an important regulator of kidney development and renal homeostasis. Increased cell invasiveness is mediated by another ubiquitin ligase target with relevance to the molecular pathogenesis of renal cell carcinoma: beta-catenin. This discovery and other recent insights into kidney cancer oncogenesis implicate convergent developmental and homeostatic signaling pathways in tumorigenesis, tumor invasiveness and metastasis.     

Familial benign hypercalcemia--from clinical description to molecular genetics.

Familial benign hypercalcemia (or familial hypocalciuric hypercalcemia), a syndrome of lifelong hypercalcemia inherited as an autosomal dominant trait, is distinct from the multiple endocrine neoplasia syndromes and other forms of inherited parathyroid disease. Familial benign hypercalcemia results from the inappropriate secretion of parathyroid hormone despite hypercalcemia, enhanced renal tubular reabsorption of calcium (independent of parathyroid hormone), and apparent tissue resistance to adverse effects of hypercalcemia. Heterozygosity for the familial hypercalcemia trait is benign, although homozygosity for the trait may lead to severe neonatal primary hyperparathyroidism. Genetic linkage studies show that most persons affected with familial hypercalcemia have a mutation on the long arm of chromosome 3 (3cen-q21), although one phenotypically indistinguishable family appears to have a mutation on the short arm of chromosome 19 (19p), and another family has neither 3q nor 19p mutations. One group has recently shown mutations in a putative parathyroid cell-surface calcium receptor that are plausible causes for the chromosome 3q variant of the familial hypercalcemia syndrome. Perhaps the other genes for this syndrome encode proteins representing hitherto-unknown regulators of systemic calcium metabolism independent of parathyroid cell calcium sensing or proteins involved in signal transduction from the calcium receptor.     

A systematic review of the natural history and biomarkers of primary lecithin:cholesterol acyltransferase deficiency

Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.     

Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma

ABSTRACT: BACKGROUND: Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney CASE PRESENTATION: A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011 CONCLUSION: we present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.     

An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation.

Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.     

Metastatic Renal Cell Carcinoma to the Thyroid Gland

ObjectiveTo examine the presentation, diagnosis, and appropriate management of renal clear cell carcinoma metastasis to the thyroid gland.MethodsWe describe a clinical case of solitary thyroid metastasis from renal clear cell carcinoma and present a comprehensive review of the related English-language literature. Common patterns of presentation and generalized overall management recommendations are evaluated and summarized.ResultsEight years after nephrectomy for renal carcinoma at age 61 years, a man presented with a thyroid mass. Cytology and histopathologic surgical findings were consistent with a solitary metastasis most compatible with metastatic clear cell carcinoma from his previous renal carcinoma. After left thyroid lobectomy and isthmusectomy, the patient remains disease-free 5 years later. Although uncommon, nearly 150 cases of clinically recognized metastatic renal cell carcinoma to the thyroid have been reported in the English-language literature. Metastatic disease from the kidney to the thyroid gland can occur more than 20 years after nephrectomy with the average time interval being 7.5 years. Obtaining a full clinical history in any patient who presents with a thyroid nodule is essential to allow consideration of possible metastatic disease from previous primary tumor. Metastatic disease to the thyroid gland can be correctly diagnosed preoperatively. If metastatic renal cancer is limited to the thyroid gland only, prompt, appropriate surgical intervention can be curative.ConclusionMetastatic renal carcinoma to the thyroid should be considered in any patient presenting with a thyroid mass and a medical history of renal cell carcinoma. (Endocr Pract. 2008;14:1040-1046)     

A linkage study of candidate loci in familial Parkinson's Disease

Background  

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Most cases are sporadic, however familial cases do exist. We examined 12 families with familial Parkinson's disease ascertained at the Movement Disorder clinic at the Oregon Health Sciences University for genetic linkage to a number of candidate loci. These loci have been implicated in familial Parkinson's disease or in syndromes with a clinical presentation that overlaps with parkinsonism, as well as potentially in the pathogenesis of the disease.     

Beta Catenin Signaling: Linking Renal Cell Carcinoma and Polycystic Kidney Disease

Loss of von Hippel-Lindau (VHL) tumor suppressor gene function occurs in familial and most sporadic renal cell carcinoma (RCC), resulting in the aberrant expression of genes that control cell proliferation, invasion and angiogenesis. The molecular mechanisms by which VHL loss leads to tumorigenesis are not yet fully defined. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteosomal degradation, implicating hypoxia response genes in RCC oncogenesis. VHL loss also allows robust RCC cell invasiveness and morphogenesis in response to hepatocyte growth factor (HGF), an important regulator of kidney development and renal homeostasis. Recent elucidation of the mechanism by which pVHL represses developmental HGF responses in adult kidney has identified another oncogenically relevant E3 ligase target: β-catenin. This discovery also further unifies recent insights into the molecular pathogenesis of polycystic kidney disease, where the identification of disease genes has revealed the integration of signaling pathways associated with primary cilia function and the regulation of cell growth and differentiation.     

Familiäre Leukämien

Leukemias and other hematological neoplasias are frequently observed in association with different genetic disorders, such as DNA repair deficiency syndromes, tumor predisposition syndromes, immunodeficiency syndromes, familial cancer syndromes and bone marrow failure syndromes, as well as in connection with several constitutional chromosomal anomalies. Recently, in families with increased leukemia incidence, constitutional mutations have been identified in genes that are also affected by somatic mutations in sporadic leukemias. In addition to these high penetrance mutations, gene alterations with low penetrance and polymorphisms seem to predispose to leukemia and/or modify the clinical course of the disease. Predisposing and modifying polymorphisms can be found in genes involved in cell proliferation, apoptosis, DNA repair, detoxification, etc. The novel findings on constitutional genetic alterations predisposing to leukemia start to close the gap between inborn and acquired genetic diseases.     

Genetics of colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. As such, it assumes a significant role in both health policy decision-making and scientific research. CRC has been a model for investigating the molecular genetics of cancer development and progression; this is in part due to the easily detectable, sequential transition of cells from normal colonic epithelium to adenoma and then to adenocarcinoma. In addition, familial syndromes that predispose to CRC, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), have significantly contributed to our understanding of the genetic mechanisms underlying CRC formation. It is now well recognized that hereditary CRC syndromes are due to germline mutations of genes that function as tumor suppressors or, less frequently, oncogenes. Accumulation of subsequent mutations in other genes with related functions results in the stepwise progression to carcinoma. It is important to note that somatic changes in similar genes are involved in the formation of sporadic CRC. The identification of these important CRC-related genes may help facilitate the early diagnosis, prevention, and treatment of CRC. This article reviews the various familial CRC syndromes along with their genetic etiology, as well as discusses the principle of genetic testing for these conditions.     

A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC.

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.     

Evaluation of canine COL4A3 and COL4A4 as candidates for familial renal disease in the Norwegian elkhound

The collagen type IV alpha3 and alpha4 chains (COL4A3 and COL4A4) are part of the specialized glomerular basement membrane in the kidney. In human these genes are responsible for Alport syndrome (a type of hereditary nephritis). Histopathological similarities between kidneys of Norwegian elkhound dogs affected with familial renal disease and human Alport syndrome were the basis for a candidate gene approach in Norwegian elkhounds. Three microsatellites-tightly linked to canine COL4A3 and COL4A4--were developed. The microsatellites were used to analyze linkage between COL4A3 and COL4A4 and familial renal disease in a Norwegian elkhound pedigree segregating this disease. Presence of one recombinant between familial renal disease and COL4A3/COL4A4 suggests that these genes are not likely candidates for familial renal disease in this breed.     

A 1.5-megabase restriction map surrounding MYC does not include the translocation breakpoint in familial renal cell carcinoma

A constitutional translocation t(3;8)(p14.2;q24.1) segregates concordantly with a familial form of renal cell carcinoma (RCC). This translocation moves the MYC oncogene, located at 8q24.1, onto the short arm of chromosome 3. Chromosome rearrangements that break in or near MYC can result in altered expression of this gene and are thought to be a primary change leading to the transformed phenotype in certain neoplastic diseases, particularly Burkitt lymphoma. Possible rearrangements of this gene in familial RCC have so far not been detected using standard Southern blot analysis. We used pulsed field gel (PFG) analysis to construct a restriction map that covers a 1500-kb region surrounding MYC, including over 1000 kb to the 5' and 550 kb to the 3' side of this gene. The 5' end of MYC contains a cluster of cleavage sites for rare-cutting restriction endonucleases, indicating the presence of an HTF island. PFG analysis of DNA containing the t(3;8) rearrangement shows that the breakpoint is not located in the mapped region, making it unlikely that MYC is involved in this form of renal cell carcinoma. The map should facilitate study of other chromosome 8 rearrangements thought to break near MYC.     

Systemic VHL gene functions and the VHL disease

The von Hippel-Lindau tumor suppressor gene (VHL) is best known as an E3 ubiquitin ligase that negatively regulates the hypoxia inducible factor (HIF). VHL mutations are the genetic defects underlying several human diseases including polycythemia, familial VHL tumor syndrome and sporadic renal cell carcinoma. VHL mutations can lead to cell-autonomous phenotypes in the tumor cells. However, non-tumor cell-autonomous functions of VHL have also been noted. VHL tumor-derived cytokines can promote inflammation and induce mobilization of endothelial progenitor cells. Up-regulation of HIF caused by VHL loss-of-function mutants, including heterozygotes, has been shown to increase the activities of hematopoietic stem cells, endothelial cells and myeloid cells. As such, systemic functions of VHL likely play important roles in the development of VHL disease.     

肾癌预后分子生物标记物研究进展

肾癌发病率约占全身恶性肿瘤的3%。肾癌组织学行为多变,预后有不确定性。外科手术可以治疗局限性肾癌,但有将近20%的局限性肾癌患者原发肿瘤切除后出现转移,而且肾癌对化疗及放疗均不敏感。基于此临床上开展了许多辅助试验的研究,并建立了许多模型来研究肾癌术后的预后,而模型的精准度一般都需要依据肾癌的生物标记物监测。有很多分子生物标记物已经证实和肾癌预后相关,如VHL、P53、Ki-67等,本文综述了肾癌预后的分子生物标记物的最新进展。