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J Am Soc Nephrol 14:359-366, 2003
© 2003 American Society of Nephrology

Molecular Cytogenetic Aberrations in Autosomal Dominant Polycystic Kidney Disease Tissue

Jean Gogusev*, Ichiro Murakami*, Mireille Doussau*, Louise Telvi{dagger}, Alexandre Stojkoski*, Philippe Lesavre* and Dominique Droz{ddagger}

*INSERM U507, Hôpital Necker, Paris, France; {dagger}Laboratoire de Cytogénétique, Hôpital St-Vincent de Paul, Paris, France; and {ddagger}Service Central d’Anatomie Pathologique, Hôpital St Louis, Paris, France.

Correspondence to Dr. Jean Gogusev, INSERM U507, Hôpital Necker, 161, Rue de Sèvres, 75015-Paris, France. Phone: 33-1-44-49-52-45; Fax; 33-1-4-566-51-33;


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Discussion
 References
 
ABSTRACT. Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-{alpha}/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35–36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression. E-mail: gogusev@necker.fr


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Discussion
 References
 
ADPKD is the most common genetic disease in humans resulting from germinal mutations of at least two causal genes (1,2). Linkage analysis studies have revealed that the mutation of PKD1 at 16p13.3 is responsible for 85%, whereas mutation of PKD2 (at 4q21-q23) causes 15% of the familial ADPKD (3–5). A small number of unlinked families to these genes has been described, suggesting existence of at least one further locus (6).

At present, knowledge of the molecular mechanisms controlling cyst formation in ADPKD patients remains limited. In fact, the mutation found in the germline is not in itself sufficient to produce a cyst, and a second sporadic event, genetic or otherwise, is also required (2,7). It is actually accepted that the second hit necessary for cysts formation inactivates the wild-type copy of the allele, which is inherited from the healthy parent (8–10). Thus, besides the germline mutation of the PKD gene(s), unknown tissue modifying factors as well as the environment might be required for cyst formation and growth (11,12). This has been illustrated by the angiotensin-converting enzyme (ACE) insertion/deletion polymorphism as a modifier influencing the progression of ADPKD in adult patients (13,14). At the cellular level, ADPKD tissue exhibits multiple changes in the basement membrane and tubular epithelium, including increased proliferation and defective sorting of membrane proteins (1,15). Noteworthy, abnormally strong polycystin immunoreactivity is observed in cystic epithelia carrying PKD gene mutation in both types of ADPKD (16). Other important cellular manifestation is the widespread apoptosis observed in both cystic and noncystic nephrons (17,18). Concerning the cytogenetic profiling of ADPKD cells, comprehensive assessment of chromosomal damage by conventional karyotyping has not yet been successful. This is due mostly to difficulties with culture of primary epithelial cells and poor chromosome morphology. However, delineation of chromosomes harboring oncogenes and/or TSG in pathologic tissues, without cell culture, became possible by the advent of comparative genomic hybridization (19). Remarkably, the powerful combination of genome-wide molecular allelotyping (LOH) and the CGH methods permitted identification of numerous recurrent clonal DNA abnormalities, particularly in tumor cell populations (19,20).

In the present study, we assessed the extent of somatic genetic changes in renal cystic tissues from patients with ADPKD by both CGH and LOH analyses. The results indicate that the predominant pattern of chromosomal alterations consist of DNA copy number changes on chromosomes 1, 9, 16, 19, and 22. These recurrent abnormalities delineate chromosomal regions that include structurally altered oncogenes and/or tumor suppressor genes involved in ADPKD pathogenesis.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Discussion
 References
 
Patients and ADPKD Tissue Samples
Polycystic kidney tissue samples were obtained from eight patients (five women and three men) whose disease has not been yet assigned to either PKD1 or PKD2. The kidneys were removed before transplantation in six patients and because of abdominal pain in the two others. The histologic analysis was performed on hematoxylin and eosin-stained sections to determine presence and the extent of dysplastic and/or neoplastic areas.

DNA Preparation from ADPKD Cysts
A series of histologically selected tissue fragments containing cysts of various sizes were removed and rinsed in PBS before the isolation of the epithelial cells layer. Polycystic kidney (PK) tissues fragments, containing at least three to five complete cysts were frozen, serially sectioned, and submitted to microdissection for DNA extraction. From each cyst, between 30 and 35 stained sections were prepared. Every ten sections (10 µm), a 5-µm section was stained with hematoxylin and eosin to guide the microdissection procedure. Samples of cysts showing areas with histologically flat hyperplasia and polypoid hyperplasia were included in the analysis (cases PK1, PK4, and PK5). Larger cysts (>2 cm in diameter) were separated from the surrounding tissue, rinsed, and used for DNA extraction according to the procedure described by Brasier and Henske (9). The isolated cystic cells were then sedimented, washed in PBS, and resuspended in solution containing 50 mM KCL, 10 mM Tris-HCl (pH 8.5), 1.5 mM MgCl2, 100 µg/ml bovine serum albumin, and 100 µg/ml proteinase K. After overnight incubation at 37°C, the mixture was extracted with phenol/chloroform (vol:vol and 24:1 chloroform:isoamyl alcohol). Normal reference DNA was extracted either from peripheral blood lymphocytes from the corresponding patient or from glomeruli scraped from the same area or from the renal large vessels.

Comparative Genomic Hybridization (CGH)
CGH was performed essentially as described (19). Briefly, the test DNA (polycystic kidney tissues) and normal reference DNA were differentially labeled with biotin-16-dUTP and digoxigenin-11-dUTP (Roche, Mannheim, Germany) respectively. Equal amounts (600 ng) of labeled polycystic tissue DNA and normal reference DNA were co-precipitated with 25 µg of unlabeled human Cot-1 DNA (Life Technologies Invitrogen Corp., Cergy-Pontoise, France). The labeled probe DNA was resuspended in 10 µl of hybridization mixture composed of 50% formamide, 2x SSC (1x SSC is 0.15 M NaCl/0.015 M sodium citrate, pH 7), and 10% dextran sulfate. After denaturation, the labeled DNA probes were co-hybridized to normal human metaphase spreads prepared by phytohemagglutinin-stimulated peripheral blood lymphocyte culture. After hybridization, biotinylated DNA sequences were visualized by fluorescein isothiocyanate (FITC)-conjugated avidin (Vector Laboratories, Burlingame, CA), whereas digoxigenin-labeled sequences were detected using mouse anti-digoxin and goat anti-mouse tetramethyl rhodamine isothyocyanate (TRITC)-coupled antibodies (Sigma, Fallavier, France). Chromosome preparations were counterstained with 4'-6-diamidino-2-phenylindole dihydrochloride (DAPI). The slides were examined with a Leica-DMRB epifluorescence microscope equipped with a triple band pass filter set (Leica, Bensheim, Germany). Images of the hybridized metaphase spreads were captured using a cooled CCD camera (Photometrics, Tucson, AZ), followed by examination of the fluorescence signals by Vysis imaging system (QUIPS, Vysis, Downers Grove, IL). At least 12 representative images were fully analyzed, and the results from these were studied separately and also combined to produce an average fluorescence ratio for each chromosome. Chromosomal regions; 1 centromere, 9 centromere, 13p telomere, 14p telomere, 21p telomere, 22 centromere and Y, were not included in the analysis because these regions tend to show artifactual CGH alterations due to large amounts of repetitive DNA (21).

Loss of Heterozygosity Analysis (LOH)
To extend the genetic deletions observed by CGH, polymorphic microsatellite markers that comprise 10-centiMorgan (cM) human index map along chromosomes showing aberrant CGH profiles were used. The allelic map was established for chromosomes, 1, 9, 16, 19, and 22 using the microsatellite primer panels ABI PRISM LMS-MD10 provided from PE Applied Biosystems (Foster City, CA). Genomic DNAs from two separate cysts of each ADPKD sample (n = 16) were analyzed by the polymorphic markers for the selected chromosomes. Paired ADPKD tissue DNA from each cyst and normal DNA were amplified in three independent PCR reactions. DNA amplification was performed using 25-ng DNA, 0.33 µM each microsatellite primer, 250 µM each dNTP, 0.5 units of Taq polymerase, 2.5 mM MgCl2, 50 mM KCl, 10 mM Tris (pH 8.3), and PE AmpliTaq Gold enzyme (PE Applied Biosystems) in a total volume of 15 µl. The PCR reaction was performed in a Gene Amp 9700 thermocycler (Applied Biosystems) as follows; denaturation time of 12 min at 95°C was followed by 35 cycles composed of 30 s of denaturation at 94°C, 30 s of annealing at 55°C, and 45 s of elongation. The extension reaction was terminated at 72°C during 10 min. Aliquots of the PCR-amplified loci were then mixed with formamide and size standard, denatured, subjected to electrophoresis, and analyzed on ABI Model 310 Genetic Analyzer. Detection and measurements of LOH was performed essentially as described (22,23). The automatically collected data were analyzed with Genescan 3.1 and Genotyper 2.0 softwares (Applera France SA, Courtaboeuf, France). Two parameters, Allelic Ratio (AR) and Allelic Imbalance (AI), were calculated for each sample. AR and AI were calculated by using the following formulae:

AR = (peak height 1)/(peak height 2).

AI = AR(test)/AR(control).

If AI showed a difference of more than 20% (AI < 0.8), the locus was further evaluated for possible allelic imbalance. Increase or decrease of AR by more than 40% in the lesion compared with the control was called LOH or amplification.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Discussion
 References
 
Renal cysts variable in size and with complex histology included in highly vascularized and inflammatory areas were found in all ADPKD tissues. Heterogeneous morphologies were observed, including flat cell hyperplasia, papillary projections, small adenomas, and cord-like arrangements of cells into the lumen. The microdissection procedure permitted extraction of DNA from the cells lining the interior wall of the smaller cysts (<1 cm in diameter) and from larger cysts wall linings, histologically identified as flat hyperplasia and polypoid hyperplasia. As shown in Figure 1, interior wall lining cells showing different histologic aspects were efficiently collected with little contamination by interstitial and/or inflammatory cells.



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  		Figure 1. Photomicrographs of hematoxylin and eosin-stained sections from autosomal dominant polycystic kidney disease (ADPKD) tissues containing area with three separate cysts (<0.5 cm in diameter) lined with cuboidal epithelium (A); area (1) of individual cyst wall lined with flat hyperplastic epithelium (B); and papillary profections (1,2,3) from cyst wall exhibiting polypoid hyperplasia (C). Serial sections of the epithelial wall linings were microdissected and used for DNA extraction. Areas of interstitial cells and inflammatory infiltrate were avoided. Original magnification, x320.

 
Comparative Genomic Hybridization
According to the CGH profiles, imbalances were detected at several chromosomes in individual cysts from all cases. In general, DNA copy number losses predominated over gain of genomic material in the majority of the cystic lesions. Chromosome imbalances detected in three separate cysts from each ADPKD tissue correlated to their histologic features are shown in Table 1. Common aberrant copy number karyotypes expressed as loss of DNA sequences were predominantly detected on chromosomes 1, 9, 12, 16, 19, and 22. Loss of DNA sequences on chromosomes 7, 12, and 13 were detected in three samples, whereas losses on chromosomes 5, 6, 10, and 14 were evidenced in two cases. For chromosome 1, under-representation of the DNA copy number was restricted to the 1p36 band in six cases; the remaining ones exhibited larger deletion of the 1p arm. The aberrant CGH profiles for chromosomes 5 and 6 indicated DNA losses located at either p or q arm. Gain of genomic material on the long arm of chromosome 3 was found in six cases, on chromosome 4 in five, and on chromosome 2 in 3 samples.


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  		Table 1. DNA copy number changes observed in eight polycystic kidney tissues. Chromosome imbalances in three individual cysts (c.) from each sample in correlation with cyst wall lining histologya
 
Loss of Heterozygosity
To supplement the CGH data, DNA from a series of sixteen individual cysts, two from each of the eight polycystic kidney (PK) tissues, was analyzed for allelic imbalances. LOH analysis was performed with 83 polymorphic microsatellite markers corresponding to selected known loci mapped at chromosomes 1, 9, 16, 19, and 22. In our experimental conditions, among the loci that demonstrated LOH, the frequency ranged up to 15%. Cumulatively, a consistent percentage of concordance between the allelic losses and the CGH imbalances was detected in individual cysts from the corresponding case. For chromosome 1, 9, and 16, allelic loss was observed at specific loci; the corresponding region exhibiting DNA copy number changes with CGH at least in one cyst from four (50%) of eight ADPKD samples (Tables 1 and 2). Comparatively, concordance of genomic losses found by CGH and LOH analyses in the same cyst at the same region for both chromosomes 19 and 22 was observed in three (37.5%) of eight cystic tissues. According to the electropherograms, definite LOH with an AI of 0.5 was found in cysts from all samples with at least one microsatellite marker positioned on chromosomes 1, 9, 16, 19, and 22. For some of the corresponding informative markers, the allelic index ranged between 0.5 and 0.75, and such allelic pattern was interpreted as an allelic imbalance. Table 2 summarizes the frequency of LOH observed at each marker locus. Allelic losses on chromosome 1 at loci D1S214 (1p36.3) and D1S207 (1p32–33) were revealed in cysts from five informative cases, whereas loss at loci D1S206 and D1S413 was detected in four ADPKD samples. Deletions seen on the 1p and 1q segments for which allelic index ranged between 0.5 and 0.75 at the same markers were detected in cysts from two different samples. Concerning the chromosome 9, clonal losses were observed at loci D9S158 (9q34), D9S290 (9q32-q43), D9S164 (9q34), and D9S150 (9q34) in cysts from five samples, whereas allelic imbalance for the same marker was detected in two polycystic tissues.


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  		Table 2. Chromosomal regions showing frequent loss of heterozygosity (LOH) in individual cysts (c) from polycystic kidneys (PK)
 
The highest LOH frequency was found on 16p13.3 segment, which was repeatedly screened in three separate PCR reactions of the cystic DNAs, by means of 13 locus specific microsatellites. Two markers confirmed loss of heterozygosity at loci D16S423 and D16S404 along the 16p13.3 segment in five ADPKD cases. Deletion of the locus D16S515 assigned to the long arm of chromosome 16 (16q22) was detected in cysts from two samples, indicating that they might have lost a larger part of this chromosome. Comparatively, definite LOH at loci D19S414 and D22S274 on chromosomal regions 19q12 and 22q13, respectively, was found in each of three separate tissue samples (Table 2). Representative electropherograms of the allelic deletion measurements, using microsatellites located at chromosomes 1, 9, 16, and 19 and the corresponding CGH profiles, are presented in Figure 2.



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  		Figure 2. Representative electropherograms showing allelic imbalances at 1p36.2–36.3, 9p15-p21, 16p13.3, and 19q13.4 chromosomal segments detected by the microsatellite markers D1S214 (case PK2), D9S290 (case PK4), D16S423 (case PK5), and D19S210 (case PK7) (left side). Heterozygous alleles are marked by arrows in the upper tracing. The lost allele is marked by a large arrow in the lower tracing. Digitized images and comparative genomic hybridization (CGH) profiles of chromosomes 1, 9, 16, and 19 showing deletion of DNA sequences located at regions showing loss of heterozygosity (LOH; right side).

 

   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
References
 
In the present report, an increased incidence of chromosome imbalances was detected by both CGH and LOH analyses in a series of cysts from ADPKD tissues, suggesting clonal genetic changes. The cystic lesions were grouped according to the CGH profile and to their allelotype established with a panel of 83 polymorphic microsattellite markers. Genomic losses, which predominated over gains, were observed by CGH, showing clustering particularly on chromosomes 1, 9, 16, 19, and 22, suggesting a recurrent nonrandom pattern of molecular cytogenetic alterations. Deletions seen by CGH on 1p, 9q, 16p, and 19q chromosomal arms were confirmed on the same segment from the same ADPKD specimen by the LOH analysis. Frequent allelic loss at two loci on the short arm of chromosome 1 was detected in cysts from seven ADPKD cases, whereas LOH on the long arm of the same chromosome was seen in two cases. Consistent number of cysts exhibited allelic losses, which were positioned on chromosomal regions 9q, 16p, and 19q. The observed allelic pattern at some loci was interpreted as an allelic imbalance rather then loss of heterozygosity (Table 2). This could be explained by contaminating nonepithelial cellular elements, including capillaries and stromal cells. On the other side, the variability in the proportion of aberrant cystic cells within the sample, as well as the restricted ability of the CGH to detect small genomic deletions, may account for the discordances observed by CGH and LOH analyses (19,21).

In light of the frequency of chromosome-specific DNA abnormalities observed, it seems that the tumor suppressor gene(s) pathway is predominant in the development and/or progression of ADPKD. Among the significant chromosome imbalances, one particular region of minimal deletion is located on the 1p35-p36 segment. Putative tumor suppressor genes on and around this region have been described, including ID3, CDC2L1, DAN, PAX7, E2F2, TNFR2, and TCEB genes at 1p (24). However, specific ADPKD-related TSG located in this region remain to be further defined because similar deletions were observed in various conditions, including parathyroid adenoma (25), neuroblastoma (26), B cell chronic lymphocytic leukemia (27), and Wilms tumor (28).

The most relevant finding observed by both CGH and LOH methods, is the under-representation of the short arm of chromosome 16p13.3, in separate cysts from five of eight analyzed samples. Allelic loss at the DS16S515 locus on 16q22 region was also detected in two ADPKD tissues, suggesting that there may be multiple genes on the entire chromosome 16, the loss of which can contribute to cystogenesis. Several candidate genes involved in the regulation of cell cycle and apoptosis have been mapped to 16p, which include TSC2 at 16p13.3 (29), ubiquitin-conjugation enzyme UBE2I at 16p13.1 (30), XPF at 16p13.2 (31), PIG7 at 16p13.1 (32), TNFR SF17 at 16p13.1 (33), and SSI-1 at 16p13 (34). A tumor suppressor function has been suggested for TSC2 gene by LOH in hamartomas in humans (35,36) and angiomyolipomas from patients with tuberous sclerosis (37), but not in renal cell carcinomas (38). In fact, it is likely that the predominant target for deletions on the 16p13 chromosomal region is the wild-type allele in cases where the other PKD1 allele contains a germline mutation, consistent with a two-hit hypothesis. In this regard, losses of large chromosomal regions containing TSG were frequently detected in various human tumors (20). These data are in agreement with previous study, in which deletions on the p arm of chromosome 16 were detected in 24% of ADPKD cysts with primers of the region 16p13 that flank the PKD1 gene (9).

A smaller group was formed by cysts showing LOH at chromosomes 9, 19, and 22q, which may also harbor ADPKD-related TSG (Table 1). Chromosome 9p has been reported as a critical region of loss in various human tumors (39,40,41). One potential candidate TSG on 9p21 segment is the CDKN2 (p16/MTS1), which encodes a 16-kD inhibitor of cyclin-dependent kinases (42). Another candidate gene located at 9q34 region is the tuberous sclerosis TSC1 gene known to act as a TSG in hamartomas from patients with tuberous sclerosis (35). In this context, simultaneous structural alterations of both TSC2 and TSC1 genes have been described in adenomatous hyperplasia (43) and micronodular pneumocyte hyperplasia concomitant with lymphangioleiomyomatosis in patients with tuberous sclerosis (44).

Other interesting areas of chromosome imbalances were detected on chromosome 19 in six ADPKD tissue samples by CGH and in cysts from three samples by the LOH analysis. Allelic losses of 19q13 chromosomal segment has been frequently reported in ovarian cancer (45), gliomas (46), oligodendrogliomas (47), and Wilms tumor (48), suggesting the location of a common tumor suppressor gene; however, none have yet been confirmed. A striking finding is the under-representation of the long arm of chromosome 22 found by CGH in seven ADPKD cases. Candidate TSG are the neurofibromatosis type 2 (NF2) gene at 22q12 (49) and hSNF5/INI1 (50). Finally, a significant DNA copy number gain was observed predominantly on chromosomes of 3q and 4q in six ADPKD samples by the CGH analysis. The possibility of an activation of tumor enhancer gene(s) at these regions related to certain ADPKD phenotypes should also be considered (7,15).

Whether specifically disrupted somatic genetic pathways are linked to ADPKD heterogeneity and progression remains to be further investigated. It is of interest that multiple cellular alterations observed in ADPKD tissues are reminiscent of those demonstrated for human tumors and may involve similar genetic steps (2,7,9,15). In this respect, an additional significant feature is the fact that the epithelium in an individual cyst is a clonal expansion, being derived from a single ADPKD cell (8). Mechanistically, it is plausible that PKD1 gene is recessive at the cellular level (as observed in inherited cancer-predisposing syndromes), with cysts forming in individuals with germ line mutation only after somatic mutation of the normal allele (2,7). In this context, our findings strongly support the multistep process of cystogenesis, each associated with loss or dosage reduction (or gain) of a specific gene that may be important for cyst initiation and progression, similar to that seen in neoplastic diseases.

In conclusion, this study reveals that ADPKD tissue exhibits a high frequency of anomalies on numerous chromosomal segments, supporting the concept that cyst development results from an accumulation of multiple genetic aberrations. In addition, these observations offer new guideposts for future efforts at positional cloning of genes that may eventually serve as novel therapeutic agents in this important clinical disorder.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 

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Received for publication August 3, 2002. Accepted for publication October 25, 2002.




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