1. Introduction
Cancer is a complex genetic disease caused by abnormal alteration (mutations) in DNA sequences that leads to dyregulation of normal cellular processes thereby driving tumor growth. The study of such causal mutations is a central focus of cancer biology for two reasons; first is to reveal the molecular mechanisms of tumorigenesis, second is to provide insight in the development of novel therapeutic and diagnostic approaches. Although hundreds of genes are known to be mutated in cancers our understanding of mutational events in cancer cells remains incomplete (Futreal PA et al, 2004). This however has widely opened the field of cancer genomics studies which aims to provide new insights into the molecular mechanisms that lead to tumorigenesis.
As we are in the era of evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative and personalized medicine, therefore, studying the Mendelian genetics of the familial forms of cancer is one approach that can set up the basis for gene-informed risk assessment and management for the patient and family. Herein we selected a Mendelian genetics form of familial cancer such as hereditary tumor syndromic endocrine neoplasias caused by highly penetrant germline mutations leading to pheochromocytoma-paraganglioma syndromes. An example of such syndromes are autosomal dominant disorders; von Hippel-Lindau (VHL); Multiple endocrine neoplasia syndrome type 1 (MEN-1), loss-of-function germline mutations in the tumor suppressor gene MEN1 increase the risk of developing pituitary, parathyroid and pancreatic islet tumors, and less commonly thymic carcinoids, lipomas and benign adrenocortical tumors. In the case of multiple endocrine neoplasia type 2 (MEN 2), gain-of-function germline mutations clustered in specific codons of the RET proto-oncogene increase the risk of developing medullary thyroid carcinoma (MTC), phaeochromocytoma and parathyroid tumors. PTEN mutations in Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Identification and characterization of germline mutations in the predisposition genes of the great majority of these syndromes has empowered the clinical practice by the retrieved genetic information which guides medical management.
This review focuses specifically on the analysis of missense mutations in oncogenes and the tumor suppressor genes, though these genes can also be mutated through a variety of other mechanisms such as DNA amplification, translocation, and deletion. Unlike synonymous or silent mutations, which do not cause amino acid changes, missense mutations are non-synonymous amino acid substitutions that are typically caused by single-base nucleotide point mutations. However, many random missense mutations are not expected to alter protein function due to plasticity built into many amino acid residues.
2. Cancer and the "two hits" of Knudson's hypothesis
Before proceeding into missense mutation in tumor suppressor gene we ought to introduce the "two hits" of Knudson's hypothesis. Alfred Knudson Jr in 1971 published his inspiring statistical analysis of the childhood cancer retinoblastoma where he found that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation (Knudson A. G. Jr, 1971). Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumors would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumors would develop late in life and in a unifocal manner. His observations led him to propose a two-hit theory of carcinogenesis. The "two hits" of Knudson's hypothesis, which has proved true for many tumors, recognized that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumor-suppressor genes (Ayerbes et al, 2008;.
3. Missense mutations in oncogenes and the tumor suppressor genes
Using the second generation sequencing approaches provided detailed information on the frequency and position of single point mutations as well as structural aberrations of cancer genomes such as small insertions and deletions, focal copy number alterations, and genomic rearrangementsm (Wood LD et al, 2007;. Jones S et al, 2008; Greenman C et al, 2007; Sjoblom T et al, 2006; Pleasance ED et al 2010a,b; Cancer Genome Atlas Research Network, 2008). The findings show that the complexity of each cancer genome is far greater than expected and that extensive variations exist between different cancer types as well as between different tumor samples of the same cancer type. Several recent studies have used the Catalogue Of Somatic Mutations In Cancer (COSMIC) database to discriminate oncogenes and the tumor suppressor genes by using the difference in their mutation patterns in order to understand oncogenesis and diagnose cancers (Forbes SA et al, 2008; Stehr H et al, 2011; Liu H, 2011). Such investigations at the systems level are currently being performed for many of oncogenes and the tumor suppressor genes as part of the Mutanom project (http://www.mutanom.org).
Stehr H
Studies of structural effects of mutations have found that disease mutations primarily occur in the protein core (Ramensky V, et al, 2002; Wang Z et al, 2001). This trend was confirmed only for the set of tumor suppressors. In contrast, core residues in oncogenes are significantly less often mutated than expected by chance. This is in agreement with Stehr H
Liu H
4. The clinical of VHL disease
von Hippel-Lindau (VHL) disease (MIM 193300) is a dominantly inherited familial cancer syndrome. It is caused by mutations in the VHL tumor suppressor gene with an incidence of 1:31-36000 live births worldwide across all ethnic backgrounds, with similar prevalence in both genders (Maher et al., 1991; Maher, et al.2004). The prevalence however was shown to be higher in some population withtin the same ethnicity such as 1:39 000 in South-West Germany and 1:53 000 in Eastern England (Maher ER et al, 1991; Neumann H et al, 1991). VHL is characterized by marked age-dependent penetrance and phenotypic variability. The factors that affect the actual clinical expression and tumor formation, including age of onset, tissue and organ-specific lesions, severity of lesions, and recurrence, are unknown. VHL main clinical manifestations are:
4.1. Hemangioplastoms
Hemangioplastoms of the central nervous system (CNS) which are typically located in the cerebellum, but can also occur at the brainstem, spinal cord, and rarely, at the lumbosacral nerve roots and supratentorial (Neumann et al., 1995). Retinal or CNS hemangioblastomas are often the earliest manifestations of VHL disease and the most common, occurring in up to 80% of patients (Maher et al., 1990b; Melmon and Rosen, 1964; Weil et al., 2003). VHL-associated cerebellar hemangioblastomas are diagnosed at a mean age of 29–33 years, much earlier than sporadic cerebellar hemangioblastomas (Hes et al., 2000a, 2000b; Wanebo et al., 2003). These lesions are rarely malignant, but enlargement or bleeding within the CNS can result in neurological damage and death (Pavesi et al., 2008). A lower incidence of CNS hemangioblastomas has been documented in specific ethnic populations (12% Finland (Niemela M et al., 1999); 5% German (Zbar B et al., 1999). Patients with cerebellar haemangioblastomas typically present with symptoms of increased intracranial pressure and limb or truncal ataxia (depending on the precise location of the tumor). Wanebo et al. (2003) showed most CNS hemangioblastomas were associated with cysts that were often larger than other hemangioblastomas.
4.2. Pheochromocytoma
Pheochromocytomas are endocrine neoplasias with intra- or extra-adrenal gland lesions that appear histologically as an expansion of large chromaffin positive cells, derived from neural crest cells (Lee et al., 2005). Seven to 18% of VHL patients are afflicted with pheochromocytomas (Crossey et al., 1994a; Garcia et al., 1997). The absence or present of this phenotype will type the VHL into type 1or 2 (A,B,C), respectively (Woodward ER et al., 1997; Hofstra RMW et al., 1996). Untreated pheochromocytomas can result in hypertension and subsequent acute heart disease, brain edema, and stroke.
4.3. Clear cell renal cell carcinoma (RCC)
Clear cell renal cell carcinoma (RCC) occurs in up to 70% of patients with VHL and is a frequent cause of death. 70% of VHL patients have the risk of developing RCC by 60 years old (Maher et al., 1990b, 1991; Whaley et al., 1994), at an average age of 44 years versus the average age of 62 years, at which sporadic RCC develops in the general population (http://www.umd.be/VHL/W_VHL /clinic.shtml). Renal cysts are common in VHL patients as well; however, unlike the completely benign cysts in the general population, renal cysts in VHL patients might degenerate into RCC (Kaelin et al., 2004). However, it is unlikely that RCC in all VHL patients originates from cysts, or that all cysts will eventually become malignant. RCC often overproduces VEGF, and thus can be very vascular (Berse et al., 1992; Sato et al., 1994; Takahashi et al., 1994).
4.4. Others clinical manifestations
VHL patient can also have low-grade adenocarcinomas of the temporal bone, also known as endolymphatic sac tumors (ELST), pancreatic tumor, and epididymal or board ligament cystadenomas (Gruber et al., 1980; Neumann and Wiestler, 1991; Maher et al., 2004; Kaelin et al., 2007). ELST in VHL cases can be detected by MRI or CT imaging in up to 11% of patients (Manski TJ, et al., 1997). Although often asymptomatic, the most frequent clinical presentation is hearing loss (mean age 22 years), but tinnitus and vertigo also occur in many cases. In addition to the inherited risk for developing cancer, VHL patients develop cystic disease in various organs including the kidney, pancreas, and liver (Hough et al., 1994; Lubensky et al., 1998; Maher et al., 1990b; Maher, 2004).
Tumor growth commonly cycled between growth and quiescent phases. Patients with numerous tumors experienced growth and quiescent phases simultaneously, suggesting that a combination of acquired genetic lesions and hormonal activity influence tumor growth.
5. VHL clinical classification:
Molecular genetic mutation and phenotypic clustering has allowed development of a clinical classification, although intra-familial variability is well recognized.
As mentioned previously VHL disease can be classified into VHL Type 1 or Type 2 depending on the phenotype. Type 1 describes those with typical VHL manifestations such as emangioblastomas and RCC, but does not include pheochromocytomas. Once a pheochromocytoma occurs the classification becomes Type 2. Type 2, accounting for 7–20% of VHL kindreds, is further subdivided into: (2A) pheochromocytomas and other typical VHL manifestations except RCC, (2B) the full spectrum of VHL disease including pheochromocytomas, RCC, and other typical VHL manifestation, and Type (2C) identifies those with familial risk of isolated pheochromocytoma (Gross D et al, 1996; Martin R, et al., 1998), although there are some kindreds without identified VHL mutation raising the possibility of another genetic locus (Woodward ER et al, 1997; Crossey et al., 1994b; Garcia et al., 1997; Mulvihill et al., 1997).
6. Morbidity and Mortality of VHL
The morbidity of VHL disease depends on the organ system involved. For example, retinal hemangioblastomas can result in retinal detachment and/or blindness (Webster et al., 1999). Mortality is often due to either metastasis of RCC or complications of CNS hemangioblastomas (Filling-Katz et al., 1991; Maher et al., 1990b; Neumann et al., 1992); however, due to improved screening guidelines, life expectancy of VHL patients has improved.
7. VHL gene and pVHL function
The human VHL gene is a 10-kb region located on the short arm of chromosome 3 (3p25.3) (Richards et al., 1993) and consists of 3 exons (Kuzmin et al., 1995; Latif et al., 1993a, 1993b): Exon1 spans codons 1–113, exon 2 spans codons 114–154, and exon 3 spans codons 155–213. Two protein products are encoded by VHL: a 30-kDa full-length protein (p30, 213 amino acids, NM_000551.2 [variant 1 mRNA]) and a shorter protein product of 19-kDa (p19, 160 amino acids NM_198156.1 [variant 2 mRNA]), which is generated by alternative translation initiation at an internal methionine at position 54 (Blankenship et al., 1999). Although evolutionary conservation of VHL sequence is very strong over most of the pVHL19 sequence, the first 53 amino acids included in pVHL30 are less well conserved and functional studies suggest that the two pVHL isoforms have equivalent effects (Woodward ER et al, 2000; Iliopoulos O et al, 1998). The VHL mRNA and protein is widely expressed in both fetal and adult tissues (Richards FM et al., 1996; Corless CL et al., 1997) and can be found in all multicellular organisms examined to date without known similarity to other proteins (van M et al., 2001). Remarkable progress has been made in elaborating the function of pVHL and the role its inactivation plays in the pathophysiology of this disorder, including dysregulation of angiogenesis and tumor formation.
Given the lack of primary sequence homology to other proteins, the function of pVHL has been derived from studying pVHL interactors and associated proteins. Roles in oxygen-dependent angiogenesis, tumorigenesis, fibronectin matrix assembly and cytoskeleton organization, cell cycle control and cellular differentiation have been proposed. The N-terminal acidic domain of VHLp30 contains eight repetitions of a five-residue acidic repeat, which are absent in VHLp19. Phosphorylation of this acidic domain participates in tumor suppression and this domain binds the Kinesin-2 adaptor KAP3, thus mediating microtubule-binding (Lolkema et al., 2005, 2007). This domain is also responsible for binding metastasis suppressor Nm23H2, a protein known to regulate dynamin-dependent endocystosis (Hsu et al., 2006). Further downstream, the β-sheet domain (residues 63–154) binds HIF0a subunits at residues 65–117 and the α-helical domain (residues 155–192) binds the Elongin B and Elongin C (Elongin BC) complex at residues 158–184 (Feldman et al., 1999). Binding of pVHL to the Elongin BC is mediated by the chaperonin TRiC/ CCT. Elongin BC binding to pVHL requires TRiC, and VHL mutations causing defects in binding to Elongin BC are associated with VHL disease (Feldman et al., 1999). pVHL inactivation leads to an overexpression of hypoxia-inducible factor (HIF) and upregulation of its targets (vascular endothelial growth factor (VEGF), erythropoietin, transforming growth factor (TGF)-beta, alpha). Whether this is the sole etiologic factor causing characteristic VHL hemangioblastoma formation remains to be clarified. Evidence also suggests that pVHL inactivation alters fibronectin extracellular matrix formation, and that pVHL may participate in cellular differentiation and cell cycle control. Ongoing studies are directed at elaborating the biologic consequences that these pathways play in the angiogenesis and tumor formation central to VHL. Additionally, VHL protein has functions that are independent of HIF-1alpha and HIF-2alpha and are thought to be important for its tumor-suppressor action, assembly of the extracellular matrix, control of microtubule dynamics, regulation of apoptosis, and possibly stabilization of TP53 proteins (Frew IJ and Krek W. 2007).
8. Molecular genetics of VHL disease
Germline mutations, including large deletions/rearrangements, in the
More than 300 germline mutations have been identified in familial VHL. These occur throughout the coding region with only a few mutations appearing in multiple families (Zbar B et al., 1996; Beroud C et al., 1996). The new mutation rate has been estimated at between 3 and 20% (Latif F et al., 1993; Richard S et al., 1994; Schimke RN et al., 2000). Although decreased penetrance has been described (Maddock IF et al., 1994), comprehensive familial molecular data have not yet been reported to clarify this rate.
There has been limited correlation between specific mutation and phenotype, although some data on genotype-phenotype correlations have been reported (Neumann H et al., 1998; Hes F et al., 2000). Such correlations have revealed that certain missense mutations confer a high risk of pheochromocytoma (VHL type 1) whereas loss of pVHL through large deletions or nonsense-mediated decay appears to be incompatible with pheochromocytoma development (VHL type 2). [Chen et al., 1995; Cybulski et al., 2002; Glavac et al., 1996; Hes et al., 2000a, 2000b; Maher et al., 1996; Neumann and Bender, 1998; Ong et al., 2007; Zbar et al., 1996].
Interestingly, missense mutations causing amino acid changes on the surface of pVHL appear to have a higher risk for pheochromocytomas than missense mutations occurring deep within the protein; surface missense mutations also appear to have a higher risk for pheochromocytomas than deletions, nonsense, and frameshift mutations [Ong et al., 2007]. Thus, pheochromocytoma development appears to be related to an intact, but altered pVHL, which has seeded the hypothesis that these mutations may induce gain-of-function possibly through a dominant negative effect [Hoffman et al., 2001; Lee et al., 2005; Maher and Kaelin, 1997; Stebbins et al., 1999]. Nordstrom-O’Brien et al., 2010, analyzed 1548 VHL families and provided a wealth of data for genotype–phenotype correlations. They found 52% had missense mutations most frequently occurred at codons 65, 76, 78, 98, splice mutations at codon 155, 158, 161, 162, and 167. 13% had frameshift, 11% had nonsense, 6% had in-frame deletions/ insertions, 11% had large/complete deletions, and 7% had splice mutations. Mutations that predict absence of functional protein (deletion, frame-shift, nonsense, and splice) are associated in 96-97% of cases with type 1 phenotype and show an increased risk of RCC (including type 2b cases). This suggests that expressed dysfunctional protein may be required for pheochromocytoma formation. Missense mutations are associated with type 2 phenotype (hemangioblastoma and pheochromocytoma +/- RCC) in 69-98% of cases (Stolle C et al., 1998; Chen F et al., 1995; Zbar B et al., 1996). While Nordstrom-O’Brien et al., found 83.5% of VHL Type 2 families mainly had missense mutations. However, this is not as high as some studies, reporting up to 96% of those with pheochromocytomas to have missense mutations (Zbar et al., 1996). Nordstrom-O’Brien et al., found low percentage of VHL Type 2 families (0.5-7%) had other types of mutation such as nonsense, frameshift, splice, in-frame deletion/insertions, and partial deletions. The small percentage of nonsense and partial deletions along with the absence of complete deletions supports theories that an intact though altered pVHL is associated with pheochromocytomas. Stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk (Ong KR et al., 2007). Although loss of heterozygosity has been reported in endolymphatic sac tumors (ELST) tumors (Kawahara N et al., 1999; Vortmeyer AO et al., 1997) no predominant mutation has been identified.
It may be difficult, however, to predict functional biologic consequences from specific point mutations without direct functional assays as reported in recent RCC
The recent characterization of the VHL protein crystal structure might suggests possible functional consequences of specific mutations. If we focus on the structure of the pVHL we can predict the effect of the mutation on the functionality of the pVHL and therefore the phenotype resulted. Mutation-specific dysfunction may depend on protein destabilization, altered interactor binding at the various pVHP binding domains or potential alteration in binding to other factors involved in tumor suppressor/activator activity. pVHL has two domains: an amino-terminal domain rich in β-sheet (the β-domain) and a smaller carboxyterminal α-helical domain (the α-domain). A large portion of the α-domain surface interacts with Elongin C, which binds to other members (e.g., Elongin B, Cul2, and Rbx1) of an SCF-like E3 ubiquitin-protein ligase complex as mentioned earlier. Obviously, loss of function VHL mutations prevents Elongin C binding and target ubiquitylation (Clifford et al., 2001). The β-domain on the other side has a macromolecular binding site targets the HIF-1α and HIF-2α regulatory subunits for proteasomal degradation. Whereas Type 1 and Type 2B mutations impair pVHL binding to Elongin C, Type 2A mutations map to the β-domain HIF-binding site and do not affect the ability of pVHL to bind Elongin C (Clifford et al., 2001). Therefore, classifying missense substitutions according to their predicted effect on pVHL structure enhances the ability to predict pheochromocytoma risk (Ong KR et al., 2007)
Nordstrom-O’Brien et al 2010 suggested that increased identification of new mutations and new patients with previously described mutations gives momentum to the search for the exact role of pVHL in its normal and mutated form. Understanding such functions and its association with specific mutations allows for identification of disease risks in individual patients. Such insight will offer improved diagnostics, surveillance, and treatment of VHL patients (Nordstrom-O’Brien et al., 2010).
Ongoing delineation of clinical subtypes may allow for better genotype-phenotype correlations, prediction of clinical progression and molecular mutation-directed clinical management. There is significant intra-familial difference in clinical expressivity and as of yet limited knowledge about modifiers of this phenotypic variation (Webster AR, et al, 1998). Prediction of the clinical course in any one patient based on molecular data is therefore difficult.
References
- 1.
Ang SO, Chen H, HirotaK et al: Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002; 32: 614-621. - 2.
Ayerbes V. M. Gallego A. G. DS Prado Fonseca. J. P. Campelo G. R. Aparicio A. L. M. Origin of renal cell carcinomas Clin Transl Oncol.2008 Nov;10 11 697 712 - 3.
Bender B. U. Gutsche M. Glasker S. et al. Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J Clin Endocrinol Metab2000 85 4568 4574 - 4.
Software and database for the analysis of mutation in VHL gene [www.umd.necker.fr:2005]. Nucleic Acids ResBeroud C. Joly D. Gallou C. et al. 1998 26 256 258 - 5.
Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol CellBerse B. Brown L. F. Van de Water L. Dvorak H. F. Senger D. R. 1992 3 211 220 - 6.
Blankenship C. Naglich J. G. Whaley J. M. Seizinger B. Kley N. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. 1999 18 1529 1535 - 7.
Cancer Genome Atlas Research Network: Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature2008 455 1061 1068 - 8.
Chen F. Kishida T. Yao M. et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat1995 5 66 75 - 9.
Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet2001 10 1029 1038 - 10.
Corless CL, Kibel AS, Iliopoulos O et al: Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic human tissues. Hum Path 1997; 28: 459-464. - 11.
Crossey P. A. Foster K. Richards F. M. ME Phipps Latif. F. Tory K. Jones M. H. Bentley E. Kumar R. Lerman M. I. Zbar B. Affara N. A. MA Ferguson-Smith Maher. E. R. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet1994a 93 53 58 - 12.
Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol GenetCrossey P. A. Richards F. M. Foster K. Green J. S. Prowse A. Latif F. Lerman M. I. Zbar B. Affara N. A. MA Ferguson-Smith Maher. E. R. 1994b 3 1303 1308 - 13.
Cybulski C. Krzystolik K. Murgia A. Gorski B. et al. Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene J Med Genet2002 E38. - 14.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature 2002; 417:949-954. - 15.
Feldman D. E. Thulasiraman V. Ferreyra R. G. Frydman J. Formation of the VHLelongin BC tumor suppressor complex is mediated by the chaperonin TRiC. Mol Cell1999 4 1051 1061 - 16.
Filling-Katz M. R. Choyke P. L. Oldfield E. Charnas L. Patronas N. J. Glenn G. M. Gorin M. B. Morgan J. K. Linehan W. M. Seizinger B. R. Zbar B. Central nervous system involvement in Von Hippel-Lindau disease. 1991 41 41 46 - 17.
Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR: The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet 2008; Chapter 10, Unit 10 11. - 18.
Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol GenetFoster K. Prowse A. van den Berg. A. et al. 1994 3 2169 2173 - 19.
Curr Opin Cell BiolFrew I. J. Krek W. Multitasking by. p. V. H. L. in tumour. suppression 2007 19 685 690 - 20.
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR. A census of human cancer genes. Nat Rev Cancer. 2004;4(3):177-83. - 21.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, et al: Patterns of somatic mutation in human cancer genomes. Nature 2007; 446:153-158. - 22.
Garcia A. Matias-Guiu X. Cabezas R. Chico A. Prat J. Baiget M. De Leiva A. Molecular diagnosis of von Hippel-Lindau disease in a kindred with a predominance of familial phaeochromocytoma. Clin Endocrinol (Oxf)1997 46 359 363 - 23.
Glavac D. Neumann H. P. Wittke C. Jaenig H. Masek O. Streicher T. Pausch F. Engelhardt D. Plate K. H. Hofler H. Chen F. Zbar B. Brauch H. Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. Hum Genet1996 98 271 280 - 24.
Gnarra J. R. Tory K. Weng Y. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet1994 7 85 90 - 25.
Gordeuk VR, Sergueeva AI, Miasnikova GY et al: Congenital disorder of oxygen-sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood2004 103 3924 3932 - 26.
Gross D. Avishai N. Meiner V. et al. Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene J Clin Endocrinol Metab1996 81 147 149 - 27.
Gruber MB, Healey GB, Toguri AG, Warren MM. Papillary cystadenoma of epididymis: component of von Hippel-Lindau syndrome. 1980 16 305 306 - 28.
Herman J. G. Latif F. Weng Y. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma Proc Natl Acad Sci USA1994 91 9700 9704 - 29.
Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene. Hum GenetHes F. Zewald R. Peeters T. Sijmons R. Links T. Verheij J. Matthijs G. Leguis E. Mortier G. van der Torren K. Rosman M. Lips C. Pearson P. van der Luijt R. 2000a 106 425 431 - 30.
Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only. J Med GenetHes F. J. Mc Kee S. MJ Taphoorn Rehal. P. van Der Luijt R. B. Mc Mahon R. van Der Smagt J. J. Dow D. Zewald R. A. Whittaker J. Lips C. J. Mac Donald. F. Pearson P. L. Maher E. R. 2000b 37 939 943 - 31.
MA Hoffman Ohh. M. Yang H. Klco J. M. Ivan M. Kaelin Jr W. G. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet2001 10 1019 1027 - 32.
Extensive mutation screening of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J Clin Endocrinol MetabHofstra R. M. W. Stelwagen T. Stulp R. P. et al. 1996 - 33.
Hough DM, Stephens DH, Johnson CD, Binkovitz LA. Pancreatic lesions in von Hippel-Lindau disease: prevalence, clinical significance, and CT findings. Am J Roentgenol1994 162 1091 1094 - 34.
Hsu T. Adereth Y. Kose N. Dammai V. Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility. J Biol Chem2006 281 12069 12080 - 35.
Iliopoulos O, Ohh M, Kaelin Jr WG: pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci USA 1998; 95: 11661-1166. - 36.
Ivan M, KaelinWG.The vonHippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001; 11:27-34. - 37.
Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, VandeWoude GF: Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA 1997; 94:11445-11450. - 38.
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, NY) 2008; 321:1801-1806. - 39.
Kaelin Jr WG. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res2004 Pt 2):6290S EOF 5S EOF - 40.
Kaelin WG. Von Hippel-Lindau disease. Annu Rev Pathol2007 2 145 173 - 41.
Kanno H. Saljooque F. Yamamoto I. et al. Role of the von Hippel-Lindau tumor suppressor protein during neuronal differentiation. Cancer Res2000 60 2820 2824 - 42.
Karchin R: Next generation tools for the annotation of human SNPs. Brief Bioinform 2009; 10:35-52. - 43.
Kawahara N, Kume H, Ueki K, et al. VHL gene inactivation in an endolymphatic sac tumor associated with von Hippel-Lindau disease. Neurology 1999; 53:208-210. - 44.
Jr Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USAKnudson A. G. 1971 68 820 823 - 45.
Kuzmin I. Duh F. M. Latif F. Geil L. Zbar B. Lerman M. I. Identification of the promoter of the human von Hippel-Lindau disease tumor suppressor gene. 1995 10 11 2185 94 - 46.
Latif F, Duh FM, Gnarra J, Tory K, Kuzmin I, Yao M, Stackhouse T, Modi W, Geil L, Schmidt L, Li H, Orcutt ML, Maher E, Richards F, Phipps M, Ferguson-Smith M, Le Paslier D, Linehan WM, Zbar B, Lerman MI. von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(11)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region. Cancer Res 1993a;53:861-867. - 47.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, and many others. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993b; 260:1317-1320. - 48.
Lee J-Y, Dong S-M, Park W-S, et al. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res1998 58 504 508 - 49.
Lee S. Nakamura E. Yang H. Wei W. MS Linggi Sajan. M. P. Farese R. V. Freeman R. S. BD Carter Kaelin. Jr Schlisio W. G. S. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. 2005 155 167 - 50.
Recent advances in genetics, diagnosis, localization and treatment of pheochromocytoma. Ann Intern MedLinehan W. M. Eisenhofer G. MM Walther Goldstein. DS 2001 134 315 329 - 51.
Liu H. Xing Y. Yang S. Tian D. Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes Oncol Rep.2011 26 6 1539 46 - 52.
Lolkema M. P. Gervais M. L. Snijckers C. M. Hill R. P. Giles R. H. EE Voest Ohh. M. Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J Biol Chem2005 80 22205 22211 - 53.
Lolkema M. P. Mans D. A. Snijckers C. M. van Noort M. van Beest M. EE Voest Giles. R. H. The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2 FEBS Lett2007 581 4571 4576 - 54.
Lubensky I. A. Pack S. Ault D. Vortmeyer A. O. Libutti S. K. Choyke P. L. MM Walther Linehan. W. M. Zhuang Z. Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis Am J Pathol1998 153 223 231 - 55.
Maddock IF, Moran A, Maher ER, et al. A genetic register for von Hippel-Lindau disease. J Med Genet 1996; 33:120-127. - 56.
Maher ER. Von Hippel-Lindau disease. Curr Mol Med2004 4 833 842 - 57.
Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J,Williams A, Ferguson-Smith MA, Morton N. Von Hippel-Lindau disease: a genetic study. J Med Genet 1991; 28:443-447 - 58.
Maher ER, Kaelin Jr WG. von Hippel-Lindau disease. Medicine (Baltimore) 1997 76 381 391 - 59.
Maher ER, Webster AR, Richards FM, Green JS, Crossey PA, Payne SJ, Moore AT. Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. J Med Genet1996 33 328 332 - 60.
Maher E. R. Yates J. R. Harries R. Benjamin C. Harris R. Moore A. T. MA Ferguson-Smith Clinical features and natural history of von Hippel-Lindau disease. Q J Med1990b 77 1151 1163 - 61.
Manski TJ, Heffner DK, Glenn GM et al: Endolymphatic sac tumors-A source of morbid hearing loss in von Hippel-Lindau disease. Jama-Journal of the American Medical Association1997 277 1461 1466 - 62.
Martin R. Hockey A. Walpole I. et al. Variable penetrance of familial pheochromocytoma associated with the von Hippel-Lindau gene mutation, S68W Mutations in brief150 Online Hum Mutat1998 71 EOF - 63.
Melmon KL, Rosen SW. Lindau’s disease. Review of the literature and study of a large kindred. Am J Med1964 36 595 617 - 64.
Mulvihill J. J. Ferrell R. E. Carty S. E. Tisherman S. E. Zbar B. Familial pheochromocytoma due to mutant von Hippel-Lindau disease gene. Arch Intern Med1997 157 1390 1391 - 65.
Neumann H. Bender B. Genotype-phenotype correlations in von Hippel-Lindau disease. J Intern Med1998 541 EOF 5 EOF - 66.
Neumann HP, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. 1991 337 1052 1054 - 67.
Neumann HP, Bausch B, McWhinney SR et al: Germ-line mutations in nonsyndromic Phaeochromocytoma. N Engl J Med 2002; 346: 1459-6621. - 68.
Neumann H. P. Eng C. Mulligan L. M. Glavac D. Zauner I. BA Ponder Crossey. P. A. Maher E. R. Brauch H. Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II 1995 274 1149 1151 - 69.
Neumann H. P. Eggert H. R. Scheremet R. Schumacher M. Mohadjer M. Wakhloo A. K. Volk B. Hettmannsperger U. Riegler P. Schollmeyer P. Central nervous system lesions in von Hippel-Lindau syndrome. J Neurol Neurosurg Psychiatry1992 55 898 901 - 70.
Neumann HP, Wiestler OD. Clustering of features and genetics of von Hippel-Lindau syndrome. 1991 258 EOF - 71.
Ng P. C. Henikoff S. Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet2006 7 61 80 - 72.
Ng PC, Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic acids research 2003; 31:3812-3814. - 73.
Niemela M. Lemeta S. Summanen P. et al. Long-term prognosis of haemangioblastoma of the CNS: impact of von Hippel-Lindau disease. Acta Neurochir1999 1147 EOF 56 EOF - 74.
Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH.Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010; 31(5):521-37. - 75.
Mutations of the von Hippel-Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. J PatholOberstrass J. Reifenberger G. Reifenberger J. et al. 1996 179 151 156 - 76.
Ong K. R. Woodward E. R. Killick P. Lim C. Macdonald F. Maher E. R. Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat2007 28 143 149 - 77.
Pavesi G. Feletti A. Berlucchi S. Opocher G. Martella M. Murgia A. Scienza R. Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: benefits, risks and outcome. J Neurosurg Sci2008 52 29 36 - 78.
Phillips J. L. BM Ghadimi Wangsa. D. et al. Molecular cytogenetic characterization of early and late renal cell carcinomas in von Hippel-Lindau disease. Chromosomes Cancer2001 31 1 9 - 79.
Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordonez GR, Bignell GR, et al: A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010a; 463:191-196. - 80.
Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, et al: A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 2010b; 463:184-190. - 81.
Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic acids research 2002; 30:3894-3900. - 82.
Richards F. M. Maher E. R. Latif F. ME Phipps Tory. K. Lush M. Crossey P. A. Oostra B. Enblad P. Gustavson K. H. Green J. Turner G. Yates J. R. W. Linehan W. M. Affara N. A. Lerman M. Zbar B. MA Ferguson-Smith Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene. J Med Genet1993 30 104 107 - 83.
Richards FM, Payne SJ, Zbar B et al: Molecular Analysis of De-Novo Germline Mutations in the von Hippel-Lindau Disease Gene. Hum Mol Gen 1995; 4:2139-2143. - 84.
Richards FM, Schofield PN, Fleming S: Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Hum Mol Gen 1996; 5: 639-644. - 85.
Richard S. Chauveau D. Chretien Y. et al. Renal lesions and pheochromocytoma in von Hippel-Lindau disease. Adv Nephrol1994 23 1 27 - 86.
Sato K. Terada K. Sugiyama T. Takahashi S. Saito M. Moriyama M. Kakinuma H. Suzuki Y. Kato M. Kato T. Frequent overexpression of vascular endothelial growth factor gene in human renal cell carcinoma. Tohoku J Exp Med1994 173 355 360 - 87.
Schimke RN, Collins D, Stolle CA. Von Hippel-Lindau syndrome. In: GeneClinics: clinical genetic information resource; www.geneclinics.org/profiles/vhl. - 88.
Shu HK, Pelley RJ, Kung HJ: Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential. Proc Natl Acad Sci USA1990 87 9103 9107 - 89.
Shuin T. Kondo K. Torigoe S. et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res1994 54 2852 2855 - 90.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al: The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314:268-274. - 91.
Stebbins CE, Kaelin Jr WG, Pavletich NP. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science1999 284 455 461 - 92.
Stehr H. Jang S. H. Duarte J. M. Wierling C. Lehrach H. Lappe M. BM Lange The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors. Mol Cancer.2011 54 EOF - 93.
Stolle C. Glenn G. Zbar B. et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat1998 12 417 423 - 94.
Takahashi A. Sasaki H. Kim S. J. Tobisu K. Kakizoe T. Tsukamoto T. Kumamoto Y. Sugimura T. Terada M. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res1994 54 4233 4237 - 95.
Tse J. Wong J. Lo-W K. et al. Molecular genetic analysis of the von Hippel-Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomas Am J Clin Pathol1997 107 459 466 - 96.
Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 1993; 9:138-141. - 97.
Vortmeyer AO, Huang SC, Koch CA, et al. Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors. Cancer Res2000 60 5963 5965 - 98.
Vortmeyer A. O. Choo D. Pack S. D. et al. Von Hippel-Lindau disease gene alterations associated with endolymphatic sac tumor. J Natl Cancer Inst1997 89 970 972 - 99.
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg2003 98 82 94 - 100.
Wang Z. Moult J. S. N. Ps protein. structure disease Human. Mutation 2001 - 101.
Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol1999 117 371 378 - 102.
Webster AR, Richards FM, MacRonald FE, et al. An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects. Am J Hum Genet1998 63 1025 1035 - 103.
Weil RJ, Lonser RR, DeVroom HL, Wanebo JE, Oldfield EH. Surgical management of brainstem hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg2003 98 95 105 - 104.
Whaley J. M. Naglich J. Gelbert L. Hsia Y. E. Lamiell J. M. Green J. S. Collins D. Neumann H. P. Laidlaw J. Li F. P. Klein-Szanto A. J. P. Seizinger B. R. Kley N. Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma Am J Hum Genet1994 55 1092 1102 - 105.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al: The genomic landscapes of human breast and colorectal cancers. Science 2007; 318:1108-1113. - 106.
Woodward ER, Buchberger A, Clifford SC et al: Comparative sequence analysis of the VHL tumor suppressor gene. Genomics 2000; 65: 253-265. - 107.
Woodward E. R. Eng C. Mc Maon R. et al. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet1997 6 1051 1056 - 108.
Woodward E. R. Eng C. Mc Maon R. et al. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL Hum Mol Genet1997 6 1051 1056 - 109.
Woodward ER, Eng C, McMahon R et al: Genetic predisposition to phaeochromocytoma: Analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet 1997; 6: 1051-1056. - 110.
Zbar B. Kaelin W. Maher E. et al. Third International Meeting on von Hippel-Lindau disease. Cancer Res1999 59 2251 2253 - 111.
Germlinemutations in the von Hippel-Lindau disease (VHL) gene in families from North American, Europe and Japan. Hum. Mutat.Zbar B. Kishida F. Chen et. al 1996 8 348 357 - 112.
Zbar B. Kishida T. Chen F. et al. Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Jap an. Hum Mutat1996 - 113.
Glavac D,Zbar B. Kishida T. Chen F. Schmidt L. Maher E. R. Richards F. M. Crossey P. A. Webster A. R. Affara N. A. MA Ferguson-Smith Brauch. H. - 114.
Germline mutations in the Von Hippel-Lindaudisease (VHL) gene in families from North America, Europe, and Japan. Hum MutatNeumann H. P. Tisherman S. Mulvihill J. J. Gross D. J. Shuin T. Whaley J. Seizinger B. Kley N. Olschwang S. Boisson C. Richard S. Lips C. H. Lerman M. Linehan W. M. 1996 8 348 357