8262540
Genetic Counseling in Renal Masses
All urologists have faced patients suffering a renal cancer asking for the occurrence of the disease in their offspring and very often the answer to this question has not been well founded from the scientific point of view, and only in few cases a familial segregation tree is performed. The grate shift seen in the detection of small renal masses and renal cancer in the last decades will prompt us to know the indications for familial studies, which and when are necessary, and probably to refer those patients with a suspected familial syndrome to specialized oncological centers where the appropriate molecular and familial studies could be done. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and would reduce costly screening procedures in at-risk members who have not inherited disease-causing mutations. This review will focus on the molecular bases of familial syndromes associated with small renal masses and the indications of familial studies in at-risk family members.
195689769
Renal cell carcinoma.
Renal cell carcinoma continues to be a difficult malignancy to treat because of its ability to spread asymptomatically and its inherent resistance to conventional chemotherapy. However, molecular genetic studies bring new insights into the pathogenesis of this disorder and may provide new targets against which novel chemotherapeutic agents could be developed. Nephron-sparing surgery is also gaining wider acceptance as favorable long-term, cancer-free survival data emerge from clinical trials. For metastatic disease, cytokine therapy continues to be the mainstay of treatment despite marginal efficacy and a significant side-effect profile.
23078788
Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data.
PURPOSE
Since the 1980s with the increased use of abdominal imaging, such as computerized abdominal tomography, renal cancer has commonly been diagnosed as an incidental mass. We analyzed the renal cancer incidence from 1973 to 1998 in the Surveillance, Epidemiology and End Results program by historic staging of localized, regional or distant disease to evaluate possible stage migration due to increased abdominal imaging.


MATERIALS AND METHODS
We used renal cancer data from the Surveillance, Epidemiology and End Results 9 registries, public use, August 2000 submission (National Cancer Institute, Bethesda, Maryland), which represents approximately 14% of the United States population. We analyzed the age adjusted renal cancer incidence from 1973 to 1998 using the 1990 American standard million population. We compared the incidence of the 3 stages of renal cancer from 1973 to 1985 and 1986 to 1998 by the chi-square test and used joinpoint regression analysis to determine whether there was a significant change in the intragroup or intergroup incidence rate with time.


RESULTS
During 1973 to 1985 the rate of localized, regional and distant renal cancer was 45%, 23% and 32% compared with 54%, 21% and 25%, respectively, from 1986 to 1998 (p = 0.45). However, the plot of incidence rate versus diagnosis year by stage showed an increasing trend in the 3 stage groups. The annual percent change in the localized, regional and distant groups was 3.7 (95% confidence interval [CI] 3.2 to 4.2), 1.9 (95% CI 1.2 to 2.6) and 0.68 (95% CI 0.1 to 1.3) per 100,000 population, respectively (p <0.05). The 3 groups also had significantly different growth rates (p <0.01).


CONCLUSIONS
There was no significant difference in stage at presentation of renal cancer diagnosed in 1973 to 1985 compared with that diagnosed in 1986 to 1998. While the lack of a decrease in distant disease despite the increased detection of regional and localized renal cancer implies that a proportion of innocuous renal cancer cases may be detected by increased abdominal imaging, the increased incidence of renal cancer in all 3 categories indicates that other factors may also be contributing to the increasing incidence of renal cancer.
31021280
The changing natural history of renal cell carcinoma.
PURPOSE
Our understanding of the natural history of renal cell carcinoma, the role of nephrectomy, the benefits of immunotherapy and the possibilities of new technologies are evolving and being integrated with advances in classification and staging. We reviewed the relevant literature to clarify these pertinent questions and provide a current review of the changes in the epidemiology, treatment and prognosis of patients with renal cell carcinoma.


MATERIALS AND METHODS
We comprehensively reviewed the peer reviewed literature on the current management of and results of treatment for renal cell carcinoma.


RESULTS
The incidence of and mortality from renal cell carcinoma have continuously increased during the last 50 years. Despite this increase in the number of new patients and consequently the number of deaths yearly the percent of those surviving for 5 years has notably improved. Factors related to improved survival include advances in renal imaging, earlier diagnosis, improved staging, better understanding of prognostic indicators, refinement in surgical technique and the introduction of immunotherapy approaches for advanced disease.


CONCLUSIONS
Currently patients with localized and metastatic renal cell carcinoma have had improvements in outlook and the therapeutic options available have expanded.
24160743
Incidental renal cell carcinoma-age and stage characterization and clinical implications: study of 1092 patients (1982-1997).
OBJECTIVES
To compare the epidemiologic, clinical, and pathologic characteristics of incidental and symptomatic renal cell carcinoma in a large series of patients, with emphasis on age distribution and its potential impact in defining groups of patients that may benefit from early detection programs.


METHODS
Records of 1092 patients with renal tumors from 1982 to 1997 were reviewed. Age, clinical presentation, and pathologic stage and grade were analyzed. Special attention was given to the age distribution and its relationship to the incidental or symptomatic diagnosis.


RESULTS
The overall mean age and proportion of patients older than 65 gradually increased (from 57 to 62.6 years and from 24.7% to 48.7%, respectively) from 1982 to 1997. The mean age in the incidental group rose steadily higher than in the symptomatic group. A progressive increase of incidental tumors from 13.0% in 1982 to 1983 to 59.2% in 1996 to 1997 was observed. A lower stage (74.3% versus 49.1%), grade (75.5% versus 56.9%), and percentage of metastases at presentation (10.4% versus 19.6%) were registered in the incidentally found neoplasms than in the symptomatic neoplasms. Eighty-two (80.4%) of 102 patients who underwent conservative surgery had incidental renal cell carcinoma.


CONCLUSIONS
Our data confirm a rapid and dramatic change in the epidemiologic and clinical characteristics of renal cancer, with an increasing number of incidentally found tumors presenting with lower stage, grade, and percentage of metastases. An unexpected but significantly higher rate of renal neoplasms was observed in older patients. The stage, grade, and patient age observed in our series of incidentally found tumors raises the question of whether to leave the current diagnostic approach unaltered, thus benefiting a subgroup of patients with clinically unrecognized and possibly indolent renal cell carcinoma, or to extend early detection programs to younger patients with potentially more aggressive tumors.
34796951
The Heidelberg classification of renal cell tumours
This paper presents the conclusions of a workshop entitled ‘Impact of Molecular Genetics on the Classification of Renal Cell Tumours’, which was held in Heidelberg in October 1996. The focus on ‘renal cell tumours’ excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic to the kidneys. The proposed classification subdivides renal cell tumours into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most commonly documented genetic abnormalities. Benign tumours are subclassified into metanephric adenoma and adenofibroma, papillary renal cell adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and renal cell carcinoma, unclassified. This classification is based on current genetic knowledge, correlates with recognizable histological findings, and is applicable to routine diagnostic practice. © 1997 John Wiley & Sons, Ltd.
17905393
Searching for the hereditary causes of renal-cell carcinoma
Families with hereditary predispositions to cancer continue to provide a unique opportunity for the identification and characterization of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal-cell carcinoma, and already genes associated with five of these syndromes have been identified — VHL, MET, FH, BHD and HRPT2. These very different genes and the biochemical pathways in which they participate raise interesting questions about the development of renal cancers and could lead to new therapeutic approaches in the near future. So, what is known about hereditary renal cancer at present?
24381690
Studying cancer families to identify kidney cancer genes.
We studied families with multiple members affected with renal cancer to delineate clinically distinct forms of inherited renal cancer, and to identify and characterize the genes responsible for these disorders. Today, cancer geneticists recognize seven clinically distinct, inherited forms of epithelial renal cancer; genes responsible for five inherited predispositions have been found. Positional cloning efforts for one kidney cancer gene are nearing completion. These discoveries will provide diagnostic tests for these diseases, a foundation for studies of the relationship between genotype and phenotype, and a basis for studies of the pathophysiology of the diverse types of epithelial renal cancer.
37716275
Molecular genetics of kidney cancer.
Tumorigenesis is a multistep process of genetic and epigenetic changes that occur in an orderly fashion The order of these changes may navigate through different steps in cancers arising from different organs/tissues. It is likely though that the final outcome is the sequential deregulation of a few key pathways of normal cell growth, namely: inactivation of tumor suppressor genes; activation of oncogenes; evasion of apoptotic cell program; and ultimately induction of angiogenesis and metastasis.’ Entry points to these genetic alterations were discovered by cloning genes disrupted by tumor-associated chromosomal translocations, harbored in cancer-associated homozygous deletions or underlying familial cancer syndromes.
3345853
The growing family of hereditary renal cell carcinoma.
features for neovascularization capacity of circulating endothelial progenitor cells. Circulation 2003; 108: 2511–2516 15. Vasa M, Fichtlscherer S, Aicher A et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1–E7 16. Hill JM, Zalos G, Halcox JP et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600 17. Tepper OM, Galiano RD, Capla JM et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002; 106: 2781–2786 18. Sutherland DR, Anderson L, Keeney M et al. The ISHAGE guidelines for CD34þ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. J Hematother 1996; 5: 213–226 19. Drueke TB. Aspects of cardiovascular burden in pre-dialysis patients. Nephron 2000; 85 [Suppl 1]: 9–14 20. De Groot K, Bahlmann FH, Sowa J et al. Uremia causes endothelial progenitor cell deficiency. Kidney Int 2004; 66: 641–646 21. Eizawa T, Murakami Y, Matsui K et al. Circulating endothelial progenitor cells are reduced in hemodialysis patients. Curr Med Res Opin 2003; 19: 627–633 22. Choi JH, Kim KL, Huh W et al. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 2004; 24: 1246–1252 23. Cohen G, Haag-Weber M, Horl WH. Immune dysfunction in uremia. Kidney Int Suppl 1997; 62: S79–S82 24. Llevadot J, Murasawa S, Kureishi Y et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001; 108: 399–405 25. Dimmeler S, Aicher A, Vasa M et al. HMG-CoA reductase inhibitors increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001; 108: 391–397 26. Bahlmann FH, de Groot K, Duckert T et al. Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 2003; 64: 1648–1642 27. Heeschen C, Aicher A, Lehmann R et al. Erythropoietin is a potent physiological stimulus for endothelial progenitor cell mobilization. Blood 2003; 102: 1340–1346 28. Bahlmann FH, de Groot K, Spandau JM et al. Erythropoietin regulates endothelial progenitor cells. Blood 2004; 103: 921–926 29. Mangi AA, Noiseux N, Kong D et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003; 9: 1195–1201
7513969
ACMG recommendations for standards for interpretation of sequence variations
These recommendations for the standardization of interpretation and reporting of sequence variations identified in the course of providing clinical laboratory services are intended (1) to provide a framework for the interpretation and reporting of such test results, and (2) to aid referring clinicians by educating them as to possible testing outcomes so that they may inform their patients and families appropriately. I. Interpretation of sequence variations Increasingly, clinical molecular laboratories are detecting novel sequence variations in the course of testing patient specimens. The certainty with which any given sequence variation is of clinical significancefallswithinaspectrumofinterpretations,rangingfromthosein which the variation is almost certainly of clinical significance to those in which it is almost certainly not. The ACMG Laboratory Practice Committee Working Group on Standards for Interpretation of Sequence Variations recommends the following categories of sequence variations for the purposes of clinical reporting. 1. Sequence variation is previously reported and is a recognized cause of the disorder. Review of the literature, central mutation databases, e.g., Human Gene Mutation Database (HGMD), or the locus-specific database, to assessthecurrentdegreeofcertaintythatthesequencevariationis causative of the disorder should be undertaken prior to reporting. Concordance studies between phenotype and genotype within a family may provide acceptable criteria in the absence of more definitive functional studies. 2. Sequence variation is previously unreported and is of the type which is expected to cause the disorder. Examples include variation that is predicted to shift the mRNA reading frame; result in the introduction of a stop codon or a missense mutation of the normal stop codon; mutate the initiation codon (ATG); alter the sequence at a splice junction, particularly the invariant AG/GT nucleotides; or delete one or more exons in such a manner as to lead to a shift in the mRNA reading frame. 3. Sequence variation is previously unreported and is of the type which may or may not be causative of the disorder. Examples include a variation that is located within a splice consensus sequence, likely to produce a cryptic splice site, likely to affect transcription, or any missense mutation. A missense mutation that leads to nonconservative substitution of an evolutionarily conserved amino acid is more likely to be causative of the disorder than a missense mutation that leads to a conservative substitution or alters an amino acid that is not evolutionarily conserved. Family studies may clarify the pathologic or benign nature of missense mutations (see III, 1 below). 4. Sequence variation is previously unreported and is probably not causative of disease. An example includes sequence variation which does not produce an amino acid substitution and which is unlikely to produce a cryptic splice site. 5. Sequence variation is previously reported and is a recognized neutral variant. Review of the literature, central mutation databases, e.g., HGMD, and the locus-specific database, to assess the current degree of certainty that the sequence variation is a recognized neutral variant should be undertaken prior to reporting. Theextenttowhichasequencevariationincategories2–4aboveis considered causative of disease may be influenced by a number of otherparameters, includingclinicalpresentation,theindividual’srisk of having the disorder, family history, other test results, and the sensitivity and specificity of the test being performed. II. Reporting of sequence variation The purpose of test reports is to state clearly the absence or presence of sequence variation and to set this information into clinical context in order to facilitate case management. Reports should be written in a style that is clear and informative to the clinician and does not require in-depth knowledge of molecular genetics to be interpretable and useful. Guidelines for report content are presented below. 1. Reports should clearly identify the gene analyzed, indicate the absence or presence of a sequence variation, and, if applicable, indicate the location of the sequence variation by nucleotide position, codons affected, and amino acid change(s). They should also include the fraction of exon sequence and intronexon boundary sequence analyzed. 2. Reports should clearly indicate the interpretative category of the test results (see above).
20186415
Molecular basis of the VHL hereditary cancer syndrome
The von Hippel–Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel–Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.
25513709
Germline mutations in the Von Hippel‐Lindau disease (VHL) gene in families from North America, Europe, and Japan
Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1–2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype‐phenotype correlations in VHL. © 1996 Wiley‐Liss, Inc.
3635075
Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.
The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC). To date, the only VCBC substrates identified are the hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha). However, pVHL is thought to have multiple functions and the significance of HIF-1alpha and HIF-2alpha regulation for tumour suppressor activity has not been defined. VHL disease is characterized by distinct clinical subtypes. Thus haemangioblastomas (HABs) and renal cell carcinoma (RCC) but not phaeochromocytoma (PHE) occur in type 1 VHL disease. Type 2 subtypes are characterized by PHE susceptibility but differ with respect to additional tumours (type 2A, PHE+HAB but not RCC; type 2B, PHE+ HAB+RCC; type 2C, PHE only). We investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Consistent effects on pVHL function were observed for all mutations within each subclass. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wild-type binding patterns with pVHL interacting proteins, suggesting that loss of other pVHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of p220 (fibronectin) binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of p220 (fibronectin) binding. Our findings are consistent with impaired ability to degrade HIF-alpha subunit being required for HAB development and RCC susceptibility.
30872757
von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.
von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ line mutation of the von Hippel-Lindau tumor suppressor gene (VHL). Tumors observed in this disorder include retinal and central nervous system hemangioblastomas, clear cell renal carcinomas and pheochromocytomas. The VHL gene product, pVHL, is a component of a ubiquitin ligase which targets the transcription factor known as hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. pVHL also plays roles in the control of extracellular matrix formation and cell-cycle exit. Different VHL mutations confer different site-specific risks of cancer. Type 2C VHL mutations confer an increased risk of pheochromocytoma without the other stigmata of VHL disease. Here we report that the products of such type 2C VHL alleles retain the ability to down regulate HIF but are defective for promotion of fibronectin matrix assembly. Furthermore, pVHL L188V, a well studied type 2C mutant, retained the ability to suppress renal carcinoma growth in vivo. These studies strengthen the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raises the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL disease.
23891833
Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding.
The eukaryotic chaperonin TRiC/CCT mediates folding of an essential subset of newly synthesized proteins, including the tumor suppressor VHL. Here we show that chaperonin binding is specified by two short hydrophobic beta strands in VHL that, upon folding, become buried within the native structure. These TRiC binding determinants are disrupted by tumor-causing point mutations that interfere with chaperonin association and lead to misfolding. Strikingly, while unable to fold correctly in vivo, some of these VHL mutants can reach the native state when refolded in a chaperonin-independent manner. The specificity of TRiC/CCT for extended hydrophobic beta strands may help explain its role in folding aggregation-prone polypeptides. Our findings reveal a class of disease-causing mutations that inactivate protein function by disrupting chaperone-mediated folding in vivo.
305206
Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterised by a predisposition to haemangioblastomas of the central nervous system (cHAB) and retina (rHAB), renal cell carcinomas (RCC), phaeochromocytomas and paragangliomas, endolymphatic sac tumours (ELST), pancreatic neuroendocrine tumours (PNET), papillary cystadenomas of epididymis, and adnexal papillary tumours of probable mesonephric origin (APMO). Renal, pancreatic, epididymal, and broad ligament cysts also occur frequently.1 It is caused by germline mutations in the VHL tumour suppressor gene on chromosome 3p25-26.2,3 VHL disease occurs with an estimated incidence of 1:36 000 live births and shows variable expression and age dependent penetrance that is almost complete by the age of 65.4 Median actuarial life expectancy of VHL subjects is reduced to 49 years, renal cell carcinoma5 or CNS haemangioblastoma6 being the most common cause of death. At present, early diagnosis and treatment of VHL associated tumours result in improved prognosis for VHL subjects.7

The disease can be diagnosed on the basis of clinical criteria in the presence of a single haemangioblastoma, phaeochromocytoma, multiple pancreatic cysts, or renal cell carcinoma in a member of a VHL family. For clinical diagnosis of isolated cases of VHL, at least two haemangioblastomas or a single haemangioblastoma in association with a visceral manifestation are required.8 In early studies, using standard Southern analysis and sequencing of the VHL coding region, disease causing mutations were detected in 38-80% of families fulfilling clinical VHL criteria.1 More recently, the development of quantitative Southern analysis (QSA) to detect partial and complete deletions has improved VHL mutation detection. QSA analysis in conjunction with direct sequencing of the coding region showed germline mutations in 100% of 93 families with definite VHL.9 However, the results implying that all cases fulfilling clinical VHL criteria are related to mutations …
33815467
Improved detection of germline mutations in the von Hippel‐Lindau disease tumor suppressor gene
von Hippel‐Lindau disease (VHL) is an inherited neoplastic disorder characterized by the development of tumors in the eyes, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis. The VHL tumor suppressor gene was identified in 1993. Initial studies reported the detection of germline mutations in the VHL gene in 39–75% of VHL families. We used tests that detect different types of mutations to improve the frequency of detection of germline mutations in VHL families. The methods included quantitative Southern blotting to detect deletions of the entire VHL gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization (FISH) to confirm deletions, and complete sequencing of the gene. Here we report that we have detected germline mutations in the VHL gene in 100% (93/93) of VHL families tested. In addition, we describe 13 novel intragenic VHL germline mutations. With the methodology described in this article, it is now possible to identify germline mutations in virtually all families with VHL. Hum Mutat 12:417–423, 1998. © 1998 Wiley‐Liss, Inc.
23379391
Von Hippel-Lindau disease germline mutations in Mexican patients with cerebellar hemangioblastoma.
OBJECT
Central nervous system (CNS) hemangioblastomas are benign vascular tumors arising either sporadically or as a manifestation of von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome. The authors studied a series of patients with CNS hemangioblastomas and their families to identify germline mutations in the VHL tumor suppressor gene and to establish a predictive testing and screening protocol.


METHODS
Patients admitted between 2002 and 2004 to the Instituto Nacional de Neurología y Neurocirugía for hemangioblastoma were prospectively enrolled, together with their at-risk family members. The authors performed the molecular analysis of the VHL gene by using polymerase chain reaction and direct genetic sequencing. All asymptomatic mutation carriers underwent genetic counseling and tumor surveillance. Ninety-eight individuals were tested for VHL mutations--23 symptomatic and 75 asymptomatic individuals belonging to 16 families. Seven of the families had definite clinical criteria of VHL disease, five had sporadic hemangioblastoma, and four had CNS hemangioblastoma combined with minor visceral signs. Molecular genetic testing identified five germline mutations in six of the definite VHL families (sensitivity 85%), but none in the possible VHL and sporadic hemangioblastoma cases; four of these mutations had been previously described and one is a novel mutation present in two unrelated families. After patients carrying the mutation were identified, they underwent clinical screening and asymptomatic VHL-related lesions were identified in 43%.


CONCLUSIONS
Genetic testing for mutations in the VHL gene is crucial in patients with CNS hemangioblastoma. The prompt identification of patients carrying the genetic mutation allows for a multidisciplinary screening protocol to decrease morbidity and mortality rates in these patients, while avoiding costly and invasive procedures for noncarriers.
24020351
Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents.
von Hippel-Lindau disease (VHL [MIM 193300]) is a heritable autosomal dominant multiple-neoplastic disorder with high penetrance. It is characterized by brain and spinal-cord hemangioblastomas, retinal angiomas, clear-cell renal carcinoma, neuroendocrine tumors and cysts of the pancreas, pheochromocytomas, endolymphatic-sac tumors, and papillary cystadenomas of the epididymis and broad ligament. Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Cases without a family history of VHL may or may not have a germline mutation in their VHL tumor-suppressor gene. We present two cases of VHL mosaicism. In each of two families, standard testing methods (Southern blot analysis and direct sequencing) identified the germline mutation in the VHL gene of the offspring, but not in their clinically affected parent. Additional methods of analysis of the affected parents' blood detected the VHL-gene mutation in a portion of their peripheral blood lymphocytes. In one case, detection of the deleted allele was by FISH, and, in the second case, the 3-bp deletion was detected by conformational sensitive gel electrophoresis and DNA sequencing of cloned genomic DNA. Mosaicism in VHL is important to search for and recognize when an individual without a family history of VHL has VHL. Patients diagnosed without family histories of the disease have been reported in as many as 23% of kindreds with VHL. Identification of individuals potentially mosaic for VHL will affect counseling of families, and these individuals should themselves be included in clinical screening programs for occult disease.
38520998
Molecular genetic analysis of von Hippel–Lindau disease
Richards FM, Webster AR, McMahon R, Woodward ER, Rose S, Maher ER (Birmingham University; Birmingham Women's Hospital, Birmingham; Addenbrooke's Hospital, Cambridge; Cambridge University, Cambridge, UK). Molecular genetic analysis of von Hippel–Lindau disease (Minisymposium: MEN & VHL). J Intern Med 1998; 243: 527–33.
18419246
The pressure rises: update on the genetics of phaeochromocytoma.
Phaeochromocytomas are neoplasias of neural crest origin arising from the adrenal medulla. Extra-adrenal phaeochromocytomas occur and may be referred to as paragangliomas, although this term is also used to describe vascular head and neck tumours, which most commonly develop at the carotid bifurcation. Historically, genetic factors have been implicated in up to 10% of phaeochromocytoma cases, but recent data suggest that germline mutations may be detected in approximately 25% of unselected cases. The most frequent causes of phaeochromocytoma susceptibility are von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), the newly delineated phaeochromocytoma-paraganglioma syndrome and, less commonly, neurofibromatosis type 1. Germline mutations in three of the succinate dehydrogenase (SDH, mitochondrial complex II) subunits (SDHD, SDHB and SDHC) cause susceptibility to head and neck paragangliomas, and may be found in approximately 20% of unselected patients. In addition, germline SDHD and SDHB mutations may cause phaeochromocytoma susceptibility with or without associated head and neck paragangliomas. Recent studies suggest that germline SDHD and SDHB mutations are an important cause of familial and isolated phaeochromocytoma. The mechanism by which SDH subunit mutations predispose to phaeochromocytomas has not been defined in detail, but dysregulation of hypoxia-responsive genes and impairment of mitochondria-mediated apoptosis have both been suggested.
18002599
Pheochromocytoma: the expanding genetic differential diagnosis.
Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
29862078
Benefits of Screening in von Hippel-Lindau Disease – Comparison of Morbidity Associated with Initial Tumours in Affected Parents and Children
Von Hippel-Lindau (VHL) is a rare autosomal dominant syndrome characterised by the association of retinal and CNS haemangioblastomas, phaeochromocytoma and renal cell carcinoma. If a child of an affected parent has inherited a VHL mutation or the parent’s mutation cannot be identified, then clinical screening is recommended. We report the clinical features in three parent-offspring pairs where the parents have presented clinically with renal cell carcinoma, phaeochromocytoma, cerebellar haemangioblastoma and retinal haemangioma, and the children have undergone pre-symptomatic screening. During the first screening a 13-year-old boy was diagnosed with bilateral phaeochromocytoma and later developed an endolymphatic sac tumour at 19 years. A right phaeochromocytoma was found in a 12-year-old girl who was screened from the age of 4 years and in a 13-year-old boy screened from 5 years of age. All children were asymptomatic at the time of diagnosis. These families demonstrate that clinical screening of children at risk of VHL can detect tumours before the first symptoms arise with a consequent reduction in morbidity. These observations strongly support the recommendation to undertake screening of the children of VHL patients.
20625725
Genetic and clinical aspects of familial renal neoplasms.
Genetic studies of families at high risk for developing malignant and benign renal neoplasms led to cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). Their significance in understanding oncogenesis extends far beyond the familial syndromes. The identification of these genes and the elucidation of their biochemical functions are likely to facilitate (1) our understanding of the full clinical spectrum of the corresponding diseases, (2) genetic counseling, and (3) rational design of effective strategies to prevent and/or treat familial and sporadic forms of these neoplasms.
24525630
Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours1–4. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8)5–6 Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7,16 and 17, and in men, by loss of the Y chromosome7. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation8–11. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D757537. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
18106462
Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto‐oncogene: Modeling studies
Missense mutations in the tyrosine kinase domain of the MET proto‐oncogene occur in selected cases of papillary renal carcinoma. In biochemical and biological assays, these mutations produced constitutive activation of the MET kinase and led to tumor formation in nude mice. Some mutations caused transformation of NIH 3T3 cells. To elucidate the mechanism of ligand‐independent MET kinase activation by point mutations, we constructed several 3D models of the wild‐type and mutated MET catalytic core domains. Analysis of these structures showed that some mutations (e.g., V1110I, Y1248H/D/C, M1268T) directly alter contacts between residues from the activation loop in its inhibitory conformation and those from the main body of the catalytic domain; others (e.g., M1149T, L1213V) increase flexibility at the critical points of the tertiary structure and facilitate subdomain movements. Mutation D1246N plays a role in stabilizing the active form of the enzyme. Mutation M1268T affects the S+1 and S+3 substrate‐binding pockets. Models implicate that although these changes do not compromise the affinity toward the C‐terminal autophosphorylation site of the MET protein, they allow for binding of the substrate for the c‐Abl tyrosine kinase. We provide biochemical data supporting this observation. Mutation L1213V affects the conformation of Tyr1212 in the active form of MET. Several somatic mutations are clustered at the surface of the catalytic domain in close vicinity of the probable location of the MET C‐terminal docking site for cytoplasmic effectors. Proteins 2001;44:32–43. © 2001 Wiley‐Liss, Inc.
9756355
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer
Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3–q43 (refs 4–6). Here we show, through a combination of mapping critical recombinants, identifying individuals with germline mutations and screening known and predicted transcripts, that this gene encodes fumarate hydratase, an enzyme of the tricarboxylic acid cycle. Leiomyomatosis-associated mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Activity of fumarate hydratase is reduced in lymphoblastoid cells from individuals with leiomyomatosis. This enzyme acts as a tumor suppressor in familial leiomyomata, and its measured activity is very low or absent in tumors from individuals with leiomyomatosis. Mutations in FH also occur in the recessive condition fumarate hydratase deficiency, and some parents of people with this condition are susceptible to leiomyomata. Thus, heterozygous and homozygous or compound heterozygous mutants have very different clinical phenotypes. Our results provide clues to the pathogenesis of fibroids and emphasize the importance of mutations of housekeeping and mitochondrial proteins in the pathogenesis of common types of tumor.
19593554
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer
Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African-American families with HLRCC. Methods: Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC. Results: We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype-phenotype correlations were identified. Conclusions: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.
22740532
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.
20694042
Inherited susceptibility to uterine leiomyomas and renal cell cancer
Herein we report the clinical, histopathological, and molecular features of a cancer syndrome with predisposition to uterine leiomyomas and papillary renal cell carcinoma. The studied kindred included 11 family members with uterine leiomyomas and two with uterine leiomyosarcoma. Seven individuals had a history of cutaneous nodules, two of which were confirmed to be cutaneous leiomyomatosis. The four kidney cancer cases occurred in young (33- to 48-year-old) females and displayed a unique natural history. All these kidney cancers displayed a distinct papillary histology and presented as unilateral solitary lesions that had metastasized at the time of diagnosis. Genetic-marker analysis mapped the predisposition gene to chromosome 1q. Losses of the normal chromosome 1q were observed in tumors that had occurred in the kindred, including a uterine leiomyoma. Moreover, the observed histological features were used as a tool to diagnose a second kindred displaying the phenotype. We have shown that predisposition to uterine leiomyomas and papillary renal cell cancer can be inherited dominantly through the hereditary leiomyomatosis and renal cell cancer (HLRCC) gene. The HLRCC gene maps to chromosome 1q and is likely to be a tumor suppressor. Clinical, histopathological, and molecular tools are now available for accurate detection and diagnosis of this cancer syndrome.
30273429
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.
20709493
Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer
Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus. Objective: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes. Methods: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. Results: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22). Conclusions: FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at-risk family members.
42777257
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
46126238
Increased risk of cancer in patients with fumarate hydratase germline mutation
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15–29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.
23566080
Analysis of fumarate hydratase mutations in a population‐based series of early onset uterine leiomyosarcoma patients
Germline mutations in fumarate hydratase (FH) gene at 1q43 predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. In HLRCC, the most common clinical features are leiomyomas of the skin and uterus, and in a subset of the families, renal cell cancer (RCC) and uterine leiomyosarcoma (ULMS) occur frequently at young age. This study was conducted to evaluate the possible contribution of FH mutations in a population‐based series of early onset (≤45 years) ULMSs. Eighty‐one cases were identified through the national cancer registry, and samples from 67 cases (83%) were available for FH mutation screening and analysis of allelic imbalance (AI) at the FH locus. Seventeen percent of tumors showed AI. In the mutation analysis, a novel missense mutation K424R was found. The mutation was also found from the patient's normal tissue. To study whether this variant has functional consequences, FH enzyme activity assay was performed in a cell model. The activity of the mutated protein was significantly reduced as compared to wild type (p = 0.009). This study shows that FH germline mutations can occur in seemingly nonsyndromic cases of ULMS (1/67, 1.5%). It appears that on the population level hereditary FH defects do play a role in pathogenesis of sporadic early onset ULMSs, albeit rarely. © 2006 Wiley‐Liss, Inc.
21667202
Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome.
The Birt-Hogg-Dubé syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dubé syndrome, in 13 Birt-Hogg-Dubé haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and approximately 9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dubé syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dubé syndrome. The Birt-Hogg-Dubé syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.
23080440
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.
37609595
Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.
20460066
Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome.
PURPOSE
Herein we describe the evaluation and management of renal tumors in Birt-Hogg-Dubé (BHD), an autosomal dominant disorder predisposing to cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal tumors.


MATERIALS AND METHODS
A total of 124 affected individuals underwent comprehensive clinical evaluation, including body computerized tomography, to determine cutaneous, pulmonary and renal manifestations of BHD. Of these individuals 14 had their renal tumors managed at our institution.


RESULTS
Of the 124 BHD affected individuals 34 (27%) had renal tumors of various histologies, most commonly hybrid oncocytic tumor and chromophobe renal carcinoma. Average age at renal tumor detection was 50.4 years and multiple tumors were found in a majority of patients. Some patients with renal tumors were identified that did not have the characteristic cutaneous hallmarks of BHD. In 4 of the 14 patients treated at our institution small (less than 3 cm) renal tumors were observed, while 10 others underwent a total of 12 renal procedures, including 4 radical and 8 partial nephrectomies. At a median of 38 months of followup 5 of these 10 patients remained free of disease, 3 had small renal tumors and 2 died of metastatic renal cancer.


CONCLUSIONS
Patients with BHD are at risk for multiple renal tumors that are often malignant and can metastasize. Individuals at risk or affected by BHD should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches. Genetic testing for this syndrome is now available.
23713328
HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome
We report here the identification of a gene associated with the hyperparathyroidism–jaw tumor (HPT–JT) syndrome. A single locus associated with HPT–JT (HRPT2) was previously mapped to chromosomal region 1q25–q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT–JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT–JT and in development of some sporadic parathyroid tumors.
26869633
Expression of Birt–Hogg–Dubé gene mRNA in normal and neoplastic human tissues
Birt–Hogg–Dubé (BHD) syndrome is an inherited autosomal genodermatosis characterized by hamartomas of the hair follicle called fibrofolliculomas and an increased risk for developing spontaneous pneumothorax, lung cysts and renal neoplasia. BHD was localized to chromosome 17p11.2 by linkage analysis in BHD families, and germline insertion/deletion and nonsense mutations in a novel gene were identified which were predicted to prematurely truncate the BHD protein, folliculin. No homology to other human proteins was found although folliculin was conserved across species. As a first step toward understanding the function of BHD in the cell and how BHD mutations can lead to the BHD phenotype, we measured the expression of BHD mRNA in normal and neoplastic human tissues by fluorescent in situ hybridization. BHD mRNA was expressed in a variety of tissues, including the skin and its appendages, the distal nephron of the kidney, stromal cells and type 1 pneumocytes of the lung, acinar cells of the pancreas and parotid gland, and epithelial ducts of the breast and prostate. In the brain, BHD mRNA was expressed in neurons of the cerebrum, and Purkinje cells in the cerebellum. BHD mRNA was also expressed in macrophage and lymphocytes in the tonsils and spleen. Tissues with reduced expression of BHD mRNA included heart, muscle and liver. BHD mRNA was expressed strongly in the proliferating epithelial strands of fibrofolliculomas, the cutaneous lesions characteristic of BHD, but not in renal tumors from BHD patients. These results indicate a wide expression pattern for BHD mRNA in many tissues, including skin, lung and kidney, which are involved in the BHD phenotype, and support a tumor suppressor role for BHD in renal cancer.
598732
Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling
Birt–Hogg–Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5′ AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt–Hogg–Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.
34481224
Inactivation of BHD in sporadic renal tumors.
Studies of families with Birt-Hogg-Dubé syndrome (BHD) have recently revealed protein-truncating mutations in the BHD gene, leading to tumorigenesis of the skin and of different cell types of kidney. To additionally evaluate the role of BHD in kidney tumorigenesis, we studied 39 sporadic renal tumors of different cell types: 7 renal oncocytomas, 9 chromophobe renal cell carcinomas (RCCs), 11 papillary RCCs, and 12 clear cell RCCs. We screened for BHD mutations and identified a novel somatic mutation in exon 13: c.1939_1966delinsT in a papillary RCC. We performed loss of heterozygosity (LOH) analysis on 28 matched normal/tumor sets, of which 10 of 28 (36%) demonstrated LOH: 2 of 6 (33%) chromophobe RCCs, 5 of 6 (83%) papillary RCCs, 3 of 12 (25%) clear cell RCCs, but 0 of 4 renal oncocytomas. BHD promoter methylation status was examined by a methylation-specific PCR assay of all of the tumors. Methylation was detected in 11 of 39 (28%) sporadic renal tumors: 2 of 7 (29%) renal oncocytomas, 1 of 9 (11%) chromophobe RCCs, 4 of 11 (36%) papillary RCCs, and 4 of 12 (33%) clear cell RCCs. Five tumors with methylation also exhibited LOH. Mutation and methylation were absent in 9 kidney cancer cell lines. Our results showed that somatic BHD mutations are rare in sporadic renal tumors. The alternatives, LOH and BHD promoter methylation, are the two possible inactivating mechanisms involved. In conclusion, unlike other hereditary kidney cancer-related genes (i.e., VHL and MET), which are cell type-specific, BHD is involved in the entire spectrum of histological types of renal tumors, suggesting its major role in kidney cancer tumorigenesis.
21661160
High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors.
The Birt-Hogg-Dubé (BHD) syndrome is an inherited genodermatosis characterized by a predisposition to hamartomatous skin lesions, pulmonary cysts, and renal carcinoma. Seventy-seven renal tumors from 12 patients with germline BHD mutations were examined by DNA sequencing to identify somatic mutations in the second copy of BHD. Sequence alterations were detected in the majority of renal tumors (41 of 77, 53%), with loss of heterozygosity at the BHD locus in a minority of additional tumors (14 of 77, 17%). The somatic mutations were distributed across the entire gene, and the majority resulted in frameshifts that are predicted to truncate the BHD protein. These results support a role for BHD as a tumor suppressor gene that predisposes to the development of renal tumors when both copies are inactivated.
19277490
Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia.
BACKGROUND
Birt-Hogg-Dubé syndrome (BHD) is a dominantly inherited predisposition for development of fibrofolliculomas, trichodiscomas, and acrochordons. Concurrent internal tumors, such as colonic polyps and renal carcinoma, have been described in patients with BHD.


OBJECTIVE
To evaluate kindreds with familial renal tumors for cutaneous manifestations of BHD.


DESIGN
One hundred fifty-two patients from 49 families underwent complete oral and skin examination. Skin lesions were identified by their clinical appearance, and the diagnosis was confirmed by results of histologic examination. Individuals underwent screening for familial renal neoplasms.


SETTING
A tertiary referral research hospital.


PATIENTS
Individuals with familial renal tumors and their asymptomatic at-risk relatives.


MAIN OUTCOME MEASURE
We determined whether any form of renal cancer is associated BHD.


RESULTS
We identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. Birt-Hogg-Dubé syndrome without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and achrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene or in the tyrosine kinase domain of the MET proto-oncogene.


CONCLUSIONS
Birt-Hogg-Dubé syndrome may be associated with familial renal tumors. Birt-Hogg-Dubé and renal tumors segregate together in an autosomal dominant fashion. Patients with BHD and their relatives are at risk for development of renal tumors. Therefore, patients with BHD and their relatives should undergo abdominal computed tomography and renal ultrasound screening for renal tumors.
29807063
Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults.
RATIONALE
Approximately 10% of patients who have a spontaneous pneumothorax have a positive family history.


OBJECTIVES
We sought to identify DNA sequence variations that confer susceptibility to pneumothoraces.


METHODS
We collected 12 families that had at least 2 first-degree relatives with a spontaneous pneumothorax. All affected family members had no obvious stigmata of known genetic disorders associated with pneumothoraces. We used haplotype analysis, DNA sequencing, and restriction fragment analysis of mutations to evaluate the individuals in these families.


MAIN RESULTS
In 2 of the 12 families the disorder cosegregated with markers flanking a candidate locus, FLCN. Sequencing the linked alleles revealed 2 mutations predicted to introduce premature stop codons in 2 of the 12 families. Most mutations in FLCN cause a rare disease, Birt-Hogg-Dubé syndrome, characterized by autosomal dominant inheritance of multiple benign skin lesions, renal tumors, pulmonary blebs, and pneumothoraces. None of the family members with the nonsense mutations had the skin manifestations of Birt-Hogg-Dubé syndrome or renal cancer. Pathologic examination of lung tissue from three affected nonsmokers revealed blebs and underlying emphysema.


CONCLUSIONS
Isolated familial spontaneous pneumothorax can be caused by mutations of the FLCN gene. Because development of a pneumothorax and/or pulmonary blebs may be the earliest or the only clinical manifestation of FLCN mutations, pulmonologists should be alert to the contribution of this gene toward this familial form of emphysema.
21671683
A 4-bp deletion in the Birt-Hogg-Dubé gene (FLCN) causes dominantly inherited spontaneous pneumothorax.
Primary spontaneous pneumothorax (PSP), a condition in which air enters the pleural space and causes secondary lung collapse, is mostly sporadic but also occurs in families. The precise etiology of PSP remains unknown, although it is associated with emphysemalike changes (bullae) in the lungs of almost all patients. We describe the results of a genetic study of a large Finnish family with a dominantly inherited tendency to PSP. A genomewide scan suggested linkage to chromosome 17p11. Screening of the best candidate gene, FLCN, revealed a 4-bp deletion in the first coding exon, which causes a frameshift that predicts a protein truncation 50 missense amino acids downstream. All carriers of the deletion had bullous lung lesions. Mutations in FLCN are also responsible for Birt-Hogg-Dubé (BHD) syndrome (a dominantly inherited disease characterized by benign skin tumors, PSP, and diverse types of renal cancer) and, rarely, are detected in sporadic renal and colorectal tumors. Unlike other FLCN mutations, the exon 4 deletion seems to be associated with bullous lung changes only with 100% penetrance. These results suggest that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema, a chronic pulmonary disease that often leads to formation of bullous lesions and lowered pulmonary function. Additionally, given the strong association of PSP and BHD, the connection between these conditions needs to be investigated further, particularly in patients with familial PSP, who may be at a greater risk of developing renal cancer.
207210347
Molecular cancer therapy: can our expectation be MET?
Altered regulation of tyrosine kinase receptors (RTKs) is frequent in solid tumours and it is often associated with the acquisition of an aggressive phenotype. Thus, therapies targeting these receptors have been proposed as molecular approaches to treat human cancers. The MET proto-oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF), controls genetic programmes leading to cell growth, invasion and protection from apoptosis. Germ-line mutations of MET in patients affected by hereditary papillary renal carcinomas (HPRC) have provided strong genetic evidences for its role in human malignancies; moreover, constitutive activation of this receptor, as a consequence of different mechanisms such as over-expression, autocrine stimulation or point mutations, is frequent in sporadic cancers. Several strategies to block the activation of MET are under development, such as the use of tyrosine kinase inhibitors or monoclonal antibodies and some of these compounds have already been used in clinical trials. In this review, we will discuss the molecular mechanisms underlying MET involvement in tumourigenesis and present pre-clinical and clinical data obtained with compounds aimed at targeting MET in the frame of cancer therapy.
1997164
Identification of the Genes for Kidney Cancer: Opportunity for Disease-Specific Targeted Therapeutics
Recent advances in understanding the kidney cancer gene pathways has provided the foundation for the development of targeted therapeutic approaches for patients with this disease. Kidney cancer is not a single disease; it includes a number of different types of renal cancers, each with different histologic features, a different clinical course, a different response to therapy, and different genes causing the defects. Most of what is known about the genetic basis of kidney cancer has been learned from study of the inherited forms of kidney cancer: von Hippel Lindau (VHL gene), hereditary papillary renal carcinoma (c-Met gene), Birt Hogg Dubé (BHD gene), and hereditary leiomyomatosis renal cell cancer (fumarate hydratase gene). These Mendelian single-gene syndromes provide a unique opportunity to evaluate the effectiveness of agents that target the VHL, c-Met, BHD, and fumarate hydratase pathways.
32894307
Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.
The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.
40827584
Practical and ethical issues with genetic screening.
Clinical hematologists are faced with a growing list of new genetic-based tools for identifying a patient's risk of disease. While many of the disease-specific tests are readily available, validation studies are required. Furthermore, genetic-based tests are being pushed to their technical limits, such as testing a single cell prior to embryo selection and transfer for couples at risk of genetic disease. As a result, misdiagnosis or misinterpretation of the data may result. As new genetic testing opportunities proliferate, the hematologist needs to be aware of the medical and legal issues surrounding their use. Furthermore, the hematologist needs to consider the psychological, ethical and social implications of this new field of genomic-based medicine.
24228610
Regulations and practices of genetic counselling in 38 European countries: the perspective of national representatives
The aim of this article is to review the national regulations and practices of genetic counselling in 38 European countries, and to examine how well they intersect the ideals of genetic counselling defined in international guidelines. Using an electronic survey, representatives of the National Societies of Human Genetics in 29 countries, and appropriate contact persons for the field of genetic counselling in 9 other countries, were asked about the regulations and practices. The answers showed that consent, confidentiality, genetic counselling in the context of prenatal diagnosis, those professionals who may perform genetic counselling, and non-directiveness were the topics most often either agreed upon among professionals or regulated in those countries. These are also among the key aspects of ideal genetic counselling, based on international guidelines. Counselling in the context of susceptibility testing for multifactorial diseases, counselling people from ethnic minorities and recontacting the counsellees, on the contrary, were topics regulated or guided by generally applied practices in only few countries. Many of the answers expressed a desire for more regulation of genetic counselling, and that more uniform practices of education and organization of genetic counselling would be welcome in Europe.
29697895
What is ideal genetic counselling? A survey of current international guidelines
The objective of this article is to review guidelines that address counselling in the context of genetic testing in order to summarise what aspects of counselling they consider most important, and to examine how they construct the ideal of genetic counselling. Guidelines were collected by examining the websites of different international professional, political, ethical and patient organisations, either previously known or found with the help of the Google search engine, and also using references listed in other studies. The most frequently mentioned topics in the collected 56 guidelines were sought, and this was carried out with the software package Qualitative Solutions and Research for Non-numerical Unstructured Data Indexing Searching and Theorizing. Topics related to genetic counselling that were mentioned in at least 30 of 56 collected documents were considered to be the most important aspects of genetic counselling. The ideal of genetic counselling is expressed in the analysed guidelines as being composed of (1) an appropriately trained professional who understands genetics and its ethical implications well; (2) relevant and objective information; (3) assurance of the counsellee's understanding; (4) psychological support; (5) informed consent; (6) confidentiality of genetic information; (7) considering familial implications; (8) appropriate handling of potential discrimination of testing; and (9) assuring autonomous decision-making by the counsellee. The ideal of genetic counselling is rather consistent in the guidelines, but there are some contradictions between the requirements of objective information-giving and adapting counselling to counsellee's circumstances.