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1.
Hum Mutat ; 34(12): 1721-6, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24123792

ABSTRACT

The advent of massive parallel sequencing is rapidly changing the strategies employed for the genetic diagnosis and research of rare diseases that involve a large number of genes. So far it is not clear whether these approaches perform significantly better than conventional single gene testing as requested by clinicians. The current yield of this traditional diagnostic approach depends on a complex of factors that include gene-specific phenotype traits, and the relative frequency of the involvement of specific genes. To gauge the impact of the paradigm shift that is occurring in molecular diagnostics, we assessed traditional Sanger-based sequencing (in 2011) and exome sequencing followed by targeted bioinformatics analysis (in 2012) for five different conditions that are highly heterogeneous, and for which our center provides molecular diagnosis. We find that exome sequencing has a much higher diagnostic yield than Sanger sequencing for deafness, blindness, mitochondrial disease, and movement disorders. For microsatellite-stable colorectal cancer, this was low under both strategies. Even if all genes that could have been ordered by physicians had been tested, the larger number of genes captured by the exome would still have led to a clearly superior diagnostic yield at a fraction of the cost.


Subject(s)
Exome , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , High-Throughput Nucleotide Sequencing , Sequence Analysis, DNA , Genetic Counseling , Genetic Testing , High-Throughput Nucleotide Sequencing/methods , High-Throughput Nucleotide Sequencing/standards , Humans , Sequence Analysis, DNA/methods , Sequence Analysis, DNA/standards
2.
Eur J Hum Genet ; 21(1): 55-61, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22692065

ABSTRACT

Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome.


Subject(s)
Agenesis of Corpus Callosum/genetics , DNA Repair-Deficiency Disorders/genetics , Glioblastoma/complications , Malformations of Cortical Development, Group II/pathology , Parotid Neoplasms/complications , Adaptor Proteins, Signal Transducing/genetics , Adenosine Triphosphatases/genetics , Agenesis of Corpus Callosum/pathology , Child , Child, Preschool , Contractile Proteins/genetics , DNA Repair Enzymes/genetics , DNA Repair-Deficiency Disorders/etiology , DNA-Binding Proteins/genetics , Female , Filamins , Glioblastoma/diagnosis , Glioblastoma/genetics , Glioblastoma/therapy , Humans , Male , Malformations of Cortical Development, Group II/genetics , Microfilament Proteins/genetics , Microsatellite Instability , Mismatch Repair Endonuclease PMS2 , MutL Protein Homolog 1 , Mutation , Nuclear Proteins/genetics , Parotid Neoplasms/diagnosis , Parotid Neoplasms/genetics , Parotid Neoplasms/therapy , Pregnancy , Syndrome
3.
Hum Mutat ; 32(4): 407-14, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21309036

ABSTRACT

Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics.


Subject(s)
Antigens, Neoplasm/genetics , Cell Adhesion Molecules/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Genetic Variation , Germ-Line Mutation/genetics , Sequence Deletion/genetics , Antigens, Neoplasm/metabolism , Base Sequence , Cell Adhesion Molecules/metabolism , DNA Methylation , Epithelial Cell Adhesion Molecule , Models, Genetic , Molecular Sequence Data , MutS Homolog 2 Protein/genetics , MutS Homolog 2 Protein/metabolism , Netherlands , Promoter Regions, Genetic , Recurrence
4.
J Mol Diagn ; 11(6): 514-23, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19779133

ABSTRACT

In this study, we developed and analytically validated a fully automated, robust confirmation sensitive capillary electrophoresis (CSCE) method to perform mutation scanning of the large SACS gene. This method facilitates a rapid and cost-effective molecular diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Critical issues addressed during the development of the CSCE system included the position of a DNA variant relative to the primers and the CG-content of the amplicons. The validation was performed in two phases; a retrospective analysis of 32 samples containing 41 different known DNA variants and a prospective analysis of 20 samples of patients clinically suspected of having autosomal recessive spastic ataxia of Charlevoix-Saguenay. These 20 samples appeared to contain 73 DNA variants. In total, in 32 out of the 45 amplicons, a DNA variant was present, which allowed verification of the detection capacity during the validation process. After optimization of the original design, the overall analytical sensitivity of CSCE for the SACS gene was 100%, and the analytical specificity of CSCE was 99.8%. In conclusion, CSCE is a robust technique with a high analytical sensitivity and specificity, and it can readily be used for mutation scanning of the large SACS gene. Furthermore this technique is less time-consuming and less expensive, as compared with standard automated sequencing.


Subject(s)
DNA Mutational Analysis/methods , Electrophoresis, Capillary/methods , Heat-Shock Proteins/genetics , DNA Mutational Analysis/economics , Electrophoresis, Capillary/standards , Humans , Mutation , Reproducibility of Results
5.
Nat Genet ; 41(1): 112-7, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19098912

ABSTRACT

Lynch syndrome patients are susceptible to colorectal and endometrial cancers owing to inactivating germline mutations in mismatch repair genes, including MSH2 (ref. 1). Here we describe patients from Dutch and Chinese families with MSH2-deficient tumors carrying heterozygous germline deletions of the last exons of TACSTD1, a gene directly upstream of MSH2 encoding Ep-CAM. Due to these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion is methylated in Ep-CAM positive but not in Ep-CAM negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense, as demonstrated here, or antisense direction, could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.


Subject(s)
Antigens, Neoplasm/genetics , Cell Adhesion Molecules/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Methylation , Exons/genetics , Inheritance Patterns/genetics , MutS Homolog 2 Protein/genetics , Sequence Deletion/genetics , Adolescent , Adult , Alleles , Asian People , Base Sequence , China , Epithelial Cell Adhesion Molecule , Family , Female , Humans , Male , Microsatellite Instability , Middle Aged , Molecular Sequence Data , Netherlands , Open Reading Frames/genetics , Pedigree , Promoter Regions, Genetic/genetics , White People/genetics
6.
Cancer Genet Cytogenet ; 179(1): 11-8, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17981209

ABSTRACT

Our group and others had previously developed a high throughput procedure to map translocation breakpoints using chromosome flow sorting in conjunction with microarray-based comparative genomic hybridization (arrayCGH). Here we applied both conventional positional cloning and integrated arrayCGH procedures to the mapping of constitutional chromosome anomalies in four patients with renal cell cancer (RCC), three with a chromosome 3 translocation, and one with an insertion involving chromosome 3. In one of these patients, who was carrying a t(3;4)(p13;p15), the KCNIP4 gene was found to be disrupted. KCNIP4 belongs to a family of potassium channel-interacting proteins and is highly expressed in normal kidney cells. In addition, KCNIP4 splice variants have specifically been encountered in RCC.


Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Kv Channel-Interacting Proteins/genetics , Translocation, Genetic , Cell Line, Tumor , Chromosome Breakage , Chromosome Mapping , Chromosomes, Human, Pair 3 , Chromosomes, Human, Pair 4 , Cloning, Molecular , Humans , In Situ Hybridization, Fluorescence , Loss of Heterozygosity , Mutagenesis, Insertional
7.
Mod Pathol ; 19(12): 1624-30, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16980941

ABSTRACT

A high degree of microsatellite instability (MSI) in colorectal cancer (CRC) is a hallmark of hereditary non-polyposis colorectal cancer (HNPCC), caused by germline defects in the mismatch repair (MMR) genes. A low degree of instability (less than 30% of the microsatellites) is seen in a subset of tumors. To clarify the significance of this low degree of MSI phenotype, we studied the differences between patients with colorectal tumors with high-level, low-level and no MSI. Colorectal tumors with no (n = 68) and low-level (n = 18) MSI of patients clinically suspected of HNPCC were compared to colorectal tumors with high-level MSI (n = 12) of patients that carry a pathogenic germline mutation in a MMR gene. Compared to tumors with no MSI, tumors with low-level MSI were classified more frequently as stage T3 or T4 (100% vs 68% respectively), and showed less immune response (P = 0.02). No significant differences in familial CRC risk were found by comparing pedigrees of these two groups of tumors. Compared to the group of tumors with high-level MSI, the group of tumors with low-level MSI had a less suspicious family history, a higher percentage of lymph node metastasis (56 vs 17%), and less immune response. Thus, with respect to genetic risks, familial CRC can be divided into two groups: Tumors with high-level MSI and tumors with low-level or no MSI. However, tumors with low-level MSI show unfavorable pathological characteristics compared to tumors with no and tumors with high-level MSI. These differences suggest a distinct underlying biology of CRC with low-level MSI.


Subject(s)
Adenocarcinoma/genetics , Adenomatous Polyposis Coli/genetics , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Microsatellite Instability , Adenocarcinoma/classification , Adenocarcinoma/pathology , Adenomatous Polyposis Coli/classification , Adenomatous Polyposis Coli/pathology , Adult , Aged , Colorectal Neoplasms/classification , Colorectal Neoplasms/pathology , DNA Mismatch Repair , DNA, Neoplasm/analysis , Female , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Middle Aged , Phenotype
8.
Hum Mutat ; 27(7): 654-66, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16683254

ABSTRACT

Rapid and reliable identification of deleterious changes in the breast cancer genes BRCA1 and BRCA2 has become one of the major issues in most DNA services laboratories. To rapidly detect all possible changes within the coding and splice site determining sequences of the breast cancer genes, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. All exons of both genes are covered by the DGGE scan, comprising 120 amplicons. We use a semiautomated approach, amplifying all individual amplicons with the same PCR program, after which the amplicons are pooled. DGGE is performed using three slightly different gel conditions. Validation was performed using DNA samples with known sequence variants in 107 of the 120 amplicons; all variants were detected. This DGGE mutation scanning, in combination with a PCR test for two Dutch founder deletions in BRCA1 was then applied in 431 families in which 52 deleterious changes and 70 unclassified variants were found. Fifteen unclassified variants were not reported before. The system was easily adopted by five other laboratories, where in another 3,593 families both exons 11 were analyzed by the protein truncation test (PTT) and the remaining exons by DGGE. In total, a deleterious change (nonsense, frameshift, splice-site mutation, or large deletion) was found in 661 families (16.4%), 462 in BRCA1 (11.5%), 197 in BRCA2 (4.9%), and in two index cases a deleterious change in both BRCA1 and BRCA2 was identified. Eleven deleterious changes in BRCA1 and 36 in BRCA2 had not been reported before. In conclusion, this DGGE mutation screening method for BRCA1 and BRCA2 is proven to be highly sensitive and is easy to adopt, which makes screening of large numbers of patients feasible. The results of screening of BRCA1 and BRCA2 in more than 4,000 families present a valuable overview of mutations in the Dutch population.


Subject(s)
Breast Neoplasms/diagnosis , DNA Mutational Analysis/methods , Electrophoresis, Polyacrylamide Gel , Genes, BRCA1 , Genes, BRCA2 , Genetic Testing/methods , Ovarian Neoplasms/diagnosis , Ambulatory Care Facilities , Female , Founder Effect , Humans , Male , Netherlands
9.
Curr Mol Med ; 4(8): 849-54, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15579032

ABSTRACT

Renal cell carcinomas (RCCs) occur in both sporadic and familial forms. In a subset of families the occurrence of RCCs co-segregates with the presence of constitutional chromosome 3 translocations. Previously, such co-segregation phenomena have been widely employed to identify candidate genes in various hereditary (cancer) syndromes. Here we survey the translocation 3-positive RCC families that have been reported to date and the subsequent identification of its respective candidate genes using positional cloning strategies. Based on allele segregation, loss of heterozygosity and mutation analyses of the tumors, a multi-step model for familial RCC development has been generated. This model is relevant for (i) understanding familial tumorigenesis and (ii) rational patient management. In addition, a high throughput microarray-based strategy is presented that will enable the rapid identification of novel positional candidate genes via a single step procedure. The functional consequences of the (fusion) genes that have been identified so far, the multi-step model and its consequences for clinical diagnosis, the identification of persons at risk and genetic counseling in RCC families are discussed.


Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 3 , Kidney Neoplasms/genetics , Translocation, Genetic , Adult , Aged , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 2 , Family , Genetic Counseling , Humans , Middle Aged , Oligonucleotide Array Sequence Analysis
10.
Genes Chromosomes Cancer ; 38(2): 107-16, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12939738

ABSTRACT

Previously, we identified a family with renal cell cancer and a t(2;3)(q35;q21). Positional cloning of the chromosome 3 breakpoint led to the identification of a novel gene, DIRC2, that spans this breakpoint. Here we have characterized the chromosome 2 breakpoint in detail and found that another novel gene, designated DIRC3, spans this breakpoint. In addition, we found that the first two exons of DIRC3 can splice to the second exon of HSPBAP1, a JmjC-Hsp27 domain gene that maps proximal to the breakpoint on chromosome 3. This splice results in the formation of DIRC3-HSPBAP1 fusion transcripts. We propose that these fusion transcripts may affect normal HSPBAP1 function and concomitant chromatin remodeling and/or stress response signals within t(2;3)(q35;q21)-positive kidney cells. As a consequence, familial renal cell cancer may develop.


Subject(s)
Carcinoma, Renal Cell/genetics , Carrier Proteins/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 3/genetics , Kidney Neoplasms/genetics , Nerve Tissue Proteins/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic/genetics , Adult , Animals , CHO Cells , Carrier Proteins/biosynthesis , Cell Line , Cell Line, Transformed , Chromosome Breakage/genetics , Cricetinae , Genetic Carrier Screening , Humans , Middle Aged , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Nerve Tissue Proteins/biosynthesis , Oncogene Proteins, Fusion/biosynthesis , RNA, Long Noncoding
11.
Cancer Genet Cytogenet ; 136(2): 95-100, 2002 Jul 15.
Article in English | MEDLINE | ID: mdl-12237231

ABSTRACT

We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2.


Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 3 , Kidney Neoplasms/genetics , Translocation, Genetic , Humans , In Situ Hybridization, Fluorescence , Karyotyping
12.
Hum Mol Genet ; 11(20): 2489-98, 2002 Oct 01.
Article in English | MEDLINE | ID: mdl-12351585

ABSTRACT

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is still pending. Additionally, a novel role for constitutional chromosome 3 translocations as risk factors for conventional RCC development is rapidly emerging. Also, several candidate loci have been mapped to other chromosomes in both familial and non-familial RCCs of distinct histologic subtypes. The MET gene on chromosome 7, for example, was found to be involved in both forms of papillary RCC. A PRCC-TFE3 fusion gene is typically encountered in t(X;1)-positive non-familial papillary RCCs and results in abrogation of the cell cycle mitotic spindle checkpoint in a dominant-negative fashion, thus leading to RCC. Together, these data turn human RCC into a model system in which different aspects of both familial and non-familial syndromes may act as novel paradigms for cancer development.


Subject(s)
Carcinoma, Renal Cell/genetics , Genetic Diseases, Inborn/genetics , Kidney Neoplasms/genetics , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Chromosomes, Human, Pair 3 , Humans , Ligases/genetics , Translocation, Genetic , Von Hippel-Lindau Tumor Suppressor Protein
13.
Cancer Genet Cytogenet ; 134(1): 6-12, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11996788

ABSTRACT

Previously, we described a family with renal cell carcinoma (RCC) and a constitutional balanced t(2;3) (q35;q21). Based on loss of heterozygosity and von Hippel-Lindau (VHL) gene mutation analyses in five tumor biopsies from three patients in this family, we proposed a multistep model for RCC development in which the familial translocation may act as a primary oncogenic event leading to (nondisjunctional) loss of the translocation-derived chromosome 3, and somatic mutation of the VHL gene as a secondary event related to tumor progression. Here, we describe the cytogenetic and molecular analysis of three novel tumors at early stages of development in two members of this family. Again, loss of derivative chromosome 3 was found in two of these tumors and a VHL mutation in one of them. In the third tumor, however, none of these abnormalities could be detected. These results underline our previous notion that loss of derivative chromosome 3 and VHL gene mutation play critical roles in familial RCC. In addition, they show that both anomalies may occur at relatively early stages of tumor development.


Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 3/genetics , Kidney Neoplasms/genetics , Translocation, Genetic , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Base Sequence , Carcinoma, Renal Cell/pathology , Cytogenetic Analysis , DNA Mutational Analysis , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Family Health , Female , Humans , Karyotyping , Kidney Neoplasms/pathology , Ligases/genetics , Loss of Heterozygosity , Male , Microsatellite Repeats , Neoplasm Staging , Pedigree , Point Mutation , Von Hippel-Lindau Tumor Suppressor Protein
14.
Hum Mol Genet ; 11(6): 641-9, 2002 Mar 15.
Article in English | MEDLINE | ID: mdl-11912179

ABSTRACT

Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth.


Subject(s)
Carcinoma, Renal Cell/genetics , Chromosomes, Human, Pair 3/genetics , Kidney Neoplasms/genetics , Neoplasm Proteins/genetics , Translocation, Genetic/genetics , Amino Acid Sequence , Base Sequence , Chromosomes, Artificial/genetics , Chromosomes, Artificial/metabolism , Chromosomes, Human, Pair 2/genetics , Cloning, Molecular , Gene Order , Genetic Markers , Genetic Predisposition to Disease , Humans , In Situ Hybridization, Fluorescence , Kidney Tubules, Proximal/metabolism , Molecular Sequence Data , Mutation/genetics , Neoplasm Proteins/metabolism , Polymerase Chain Reaction , von Hippel-Lindau Disease/genetics
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