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Keywords:

  • papillary renal cell tumor;
  • chromosome 1q gain;
  • tumor progression;
  • array CGH;
  • gene expression

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Papillary renal cell tumors (RCT) make up a cytomorphologically and biologically heterogeneous group of kidney cancers including renal cell adenomas (RCA) and renal cell carcinomas (RCC). To find genetic markers landmarking the tumor progression, we have evaluated the genetic alterations obtained by karyotyping, chromosomal and array-CGH and compared with the cytological characteristics and biological behavior of 60 papillary RCTs. Based on the genetic and clinical data, we have separated 3 groups of tumors and proposed 3 genetically defined developmental stages of papillary RCTs. Papillary RCAs are characterized by combined trisomy of chromosomes 7 and 17, whereas papillary RCCs displayed additional trisomies of 3q, 8q, 12q, 16q and 20q. In addition to the genetic changes occurring in the second group, the third group of tumors was characterized by 1q gain and 6q, 8p, 9p and 14q losses. Kaplan-Meier analysis revealed a significant association between chromosome 1q gain and deadly outcome of the disease. The cytomorphological variation and size of tumors in the second and third groups did not correlate with the clinical outcome. Therefore, we suggest that our genetic classification system landmarking papillary RCA, papillary RCC without and with progression offer a better system to characterize the tumor biology of clinical significance than a cellular/morphological classification. © 2008 Wiley-Liss, Inc.

Papillary renal cell tumors (RCT) account only for 10% of renal cell cancers in surgical series. However, the number of small papillary lesions accompanying clinically recognized tumors or being detected incidentally by modern imaging analysis is much higher than that of all other types of renal tumors together. In two comprehensive histological studies working up the entire nephrectomy specimens with sporadic and hereditary papillary RCTs, an average of 42 and over 1,000 papillary lesions has been found per kidneys, respectively.1, 2 In 4,309 consecutive autopsies, 725 macroscopically detectable adenomas occurring in 305 kidneys have been described.3 Clinicopathological studies suggested that papillary renal cell carcinomas (RCC) have a better prognosis with ∼80% survival rate after 5 years follow-up than conventional RCCs.4, 5 As no markers distinguishing between papillary renal cell adenomas (RCA) and papillary RCCs are available, several papillary RCAs might have been included in these studies.

Papillary RCTs have been identified as a genetic entity nearly 20 years ago.6 This type of kidney cancer display trisomy of chromosomes 7 (85%) and 17q (92%) and trisomies of 3q, 8, 12, 16q and 20q in 24%–67% of the cases.7–9 It was proposed that combined trisomy of chromosomes 7 and 17 are the primary genetic changes in papillary RCAs, and trisomies at chromosome 3q, 8p, 12q, 16q and 20q mark papillary RCCs.10, 11

We have now analyzed the genetic alterations by karyotyping and chromosomal CGH in 60 papillary RCTs in relation to tumor progression. We found that duplication of chromosome 1q21-qter region and deletions at chromosomes 6q, 8p, 9p and 14q are strongly associated with the progression of the disease. To delineate the smallest overlapping duplication at chromosome 1q marking the genes involved in tumor progression, we have analyzed 13 papillary RCTs without progression and 7 papillary RCCs with fatal clinical outcome by applying a full tiling path BAC-array. We have also analyzed the same set of tumors for expression of genes at the chromosome 1q region.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Tumor samples and karyotyping

The sample set consists of 60 papillary RCTs obtained from 32 patients (Supp. Info. Table I). This material represents all developmental and clinical stages of papillary RCTs from small initial tumors of 2 mm in diameter to large tumors of 16 cm with metastatic tumor growth. Multiple tumors were obtained from 2 patients with hereditary papillary RCTs and germ line mutations of the MET gene.12 Fresh normal and tumor tissues were obtained immediately after nephrectomy. A part of the tumor was immediately snap-frozen in liquid nitrogen and stored at −80°C. Another part of tumor tissue was used for cell culture and cytogenetic analysis with G-banding as described previously.6 Results of the karyotyping of 26 of the 60 tumors were published earlier.7 The collection and use of all tissue samples for this study was approved by the Ethics Committee of the University of Heidelberg.

Histological diagnosis

The histological diagnosis was established according to the Heidelberg Classification of Renal Cell Tumors.13 Grading was performed based on the 3 scales of grading system, where G1 and G2 corresponds to Fuhrman G1 and G2, whereas G3 to Fuhrmann G3–G4. We have characterized the cytological features of papillary RCTs according to the criteria showed in Figure 1. Tumors composed entirely of small cuboidal cells with scanty “clear” or eosinophilic cytoplasm resembling blastemal cells were called small basophilic (SB) (Fig. 1a) or small eosinophilic (SE) cell type, respectively. Tumors having large columnar cells with abundant granular-eosinophilic but sometimes pale eosinophilic or basophilic cytoplasm were designed as large eosinophilic (LE) or large basophilic (LB) cell type (Fig. 1c). Tumors composed of cells in size between the small and large types were called medium cell type (Fig. 1b). The cells of medium size displayed either eosinophilic (ME), basophilic (MB) or clear (MC) cytoplasm. The rest of tumors was split into 2 additional groups, namely those consisted of a mixture of small and medium or medium and large cells. However, it should be acknowledged that there is no strict border between small, medium or large cells with clear, basophilic or eosinophilic cytoplasma but a continuous spectrum in cell size and staining intensity. The clinicopathological and genetic data are summarized in Supporting Information Table I.

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Figure 1. Histological pictures of papillary RCTs. (a), (b) and (c) represents the small cell, medium cell and large cell papillary RCTs, respectively. (d) Papillary RCC composed of medium sized eosinophilic cells showing nuclear Grade 2. The patient is alive without disease. (e) Papillary RCC composed of small eosinophilic cells. The papillary stalks are heavily infiltrated by foamy cells. The patient died because of metastatic tumor within 1 year. (f) Lymph node metastasis of a papillary RCC showing small eosinophilic cells. The patient died one and half year after the nephrectomy because of metastatic disease. To be able to compare the cellular characteristics, all pictures have the same microscopic and optical magnification.

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DNA and RNA extraction

DNA was extracted from tumor cells in short-term culture and corresponding normal kidney tissues by phenol/chloroform treatment after proteinase K digestion, precipitated in ethanol and dissolved in a TE buffer. For gene expression analysis, the frozen tumor and normal kidney tissue samples were homogenized in TRIzol reagent (Invitrogen, Karlsruhe, Germany) and RNA was extracted according to the manufacturer's instructions. The quality and quantity of RNA was assessed by spectrophotometry and denaturing agarose gel electrophoresis.

Chromosomal CGH

DNA of a healthy donor (reference DNA) was labeled with digoxigenin-11-dUTP and DNA from papillary RCTs was labeled with biotin-16-dUTP (Roche Diagnostics, Mannheim, Germany) using standard nick translation protocol.14 CGH analysis was performed as described previously with minor modifications.15 The threshold values for detection of genomic imbalances were 0.75 for losses and 1.25 for gains, respectively.

Full tiling path BAC-array CGH analysis

The karyotyping and chromosomal CGH of the 60 papillary RCTs identified the duplication of the entire long-arm of chromosome 1 in some cases. To search for a smaller region of duplication we have analyzed 20 cases including all papillary RCCs with deadly outcome and also tumors from the second group by full tiling path BAC array. The CGH hybridizations using microarray containing of 32.000 bacterial artificial chromosomes were performed and analyzed in Nijmegen Centre for Molecular Life Sience (NCMLS) by one of the authors (AS) according to the procedure described elsewhere.16, 17 In brief, 500 ng of sonicated tumor and corresponding normal kidney DNA were labeled by random priming using Cy3-dUTP and Cy5-dUTP, respectively (Amersham Biosciences, Freiburg, Germany). If corresponding DNA was not available, labeled tumor DNA was sex-matched with a pool of reference DNA. The labeled test and reference DNA samples were matched, mixed with human COT1-DNA (Invitrogen), coprecipitated and resuspended in hybridization solution containing 50% formamide, 10% dextran sulfate, 2× SSC, 4% SDS and 10 μg/μL of yeast tRNA (Invitrogen). DNA samples were denaturated and applied on GeneTac Hybridization Station (Genomic Solutions). Hybridization and posthybridization washing procedures were performed according to the manufacturer's instructions. Thereafter the arrays were scanned using a GenePix Autoloader 4200AL laser scanner (Axon Instruments). Spot identification and 2-color fluorescence intensity measurements were obtained using the GenePix 5.0 software and all data were transferred into a database for subsequent analysis on MAD server as described previously.17

Gene expression analysis

Total RNA was further purified by RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol and the quality was assessed by spectrophotometry and denaturating agarose electrophoresis. The cRNA synthesis, hybridization and primary statistical analysis were performed by the Core Facility of the EMBL, Heidelberg, Germany. Normal fetal and adult kidneys and RCT were hybridized once using Affymetrix HG U133 plus 2.0 array. Affymetrix raw data (CEL files) were used as input files for further analysis. Processing and normalization were performed according to Robust Multichip average algorithm implemented as RMA package in R-Bioconductor (http://www.r-project.org).18 For further analysis, RMA-normalized values were used. Microarray data used in this study are available at the public microarray database Gene Expression Omnibus (series record GSE11151). To find a marker genes for a different tumor groups the Gene Set Enrichment Analysis (GSEA) was performed.19 To compare the sample classes of papillary RCCs without and with progression, we have generated a rank-ordered list of marker genes using GSEA (www.broad.mit.edu/gsea).

Quantitative RT-PCR

Two micrograms of total RNA was reverse transcribed with SuperScript II Reverse Transcriptase (Invitrogen) in 25 μL reaction volume. Six microliters of 1:16 diluted cDNA was amplified with 0.5 μM of each forward and reverse primer and 7.5 μL of the Platinum SYBR Green qPCR SuperMix UDG kit (Invitrogen) in 15 μL final volume. The PCR was performed in the Opticon Real-Time PCR Machine (MJ Research Inc., Watertown, MA.). Primer sequences and PCR conditions used for screening the genes listed in Table I, for GAPDH and ACTB are available upon request. Specificity of the PCR products was verified by analysis of melting curves generated at the end of the cycles. For relative quantification, standard curves were performed from a 5-step dilution series of pooled normal kidney cDNA for both gene specific and also GAPDH and ACTB reactions. The relative expression level was calculated by dividing the gene specific expression with the parallel GAPDH and ACTB expression.

Table I. List of Genes from Chromosome 1q Analyzed by Quantitative RT-PCR
Gene symbolFull name
ADORA1Adenosine A1 receptor
APOA1BPApolipoprotein A-I binding protein
BCANBrevican
C1orf54Chromosome 1 open reading frame 54
C1orf56Chromosome 1 open reading frame 56
C1orf107Chromosome 1 open reading frame 107
HAX1HCLS1 associated protein X-1
HDGFHepatoma-derived growth factor (high-mobility group protein 1-like)
KIF14Kinesin family member 14
MRPL24Mitochondrial ribosomal protein L24
MRPS14Mitochondrial ribosomal protein S14
MTX1Metaxin 1
NEK2NIMA (never in mitosis gene a)-related kinase 2
PRCCPapillary renal cell carcinoma (translocation-associated)
TNFAIP8L2Tumor necrosis factor, alpha-induced protein 8-like 2
UCK2Uridine-cytidine kinase 2

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Copy number alterations mark three genetic stages of papillary renal cell tumors

Our karyotyping, chromosomal CGH and tiling BAC-array CGH analysis confirmed the specificity of chromosome 7 and 17 changes in papillary RCTs (Table II; Supp. Info. Table I). A combination of trisomy 7 and 17 was seen in 52 of the 60 papillary RCTs (87%). Six additional tumors revealed gain of chromosome 17, one case showed gain of chromosome 7 and only one of the 60 tumors showed no changes of these chromosomes. On the basis of the complexity of additional chromosomal/DNA changes, we have divided the papillary RCTs into 3 groups (Table II). In the first group (n = 18), all tumors display a combined trisomy of chromosomes 7 and 17 and also a frequent loss of the Y chromosome in tumors of male patients. No any other genomic changes were detected in this group. The second group of tumors (n = 33) showed the alterations characteristic for the first group combined with trisomies of chromosome 3q, 8q, 12q, 16q and 20q. In addition to the genetic alterations found in the second group, the third group of papillary RCCs (n = 9) displayed duplication/gain of chromosome 1q (Fig. 2), deletion/loss of 6q, 9p and 14q and also some other chromosomal losses. Loss of the Y chromosome or gain/structural changes of the X chromosome occurred at high frequency in each group making up the alteration of these 2 chromosomes in 83% and 71% of the 46 male and 14 female tumors, respectively.

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Figure 2. Representative array CGH profile of 2 papillary RCC showing loss of chromosome 1p and gain of 1q sequences.

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Table II. Pertinent Data of the Three Developmental Stages of Papillary Renal Cell Tumors
GroupNo. casesChromosomal changes (%)Cell typeGrading (%)Size (mm)
+7+17+3+8+12+16+20+1q-6q-9p-14qSmallMediumLargeMixG1G2G3
I18100100         11 (7)(7) 7100  2–55
II3394100249335248    14 (12)7 (12) 126139 2–120
III944661133555544783344111 (3)2 (4)1 (3)5 445625–160

Overlapping clinicopathological parameters in genetic stages

The clinicopathological data of the tumors included in this study are shown in Table II and Supporting Information Table I. We have classified all the 18 tumors in the first group as T1, N0, M0, G1. Based on the criteria shown in Figure 1, 11 tumors were described as SB or SE, and 7 tumors as mixed cell-type with combination of SB/SE and ME cellular characteristics. The size of tumors varied from 2 mm to 55 mm.

In the second group, we found 18 T1, N0, M0, G1 and 8 T1, N0, M0, G2 tumors, whereas 2 of the tumors were T2, N0, M0, G1 and 5 cases were T2, N0, M0, G2. The cellular characteristics were varied from SB cells towards ME cells. Fourteen tumors showed only SB or SE cells, 7 cases ME cells and 12 cases a mixture of SB/SE and ME/MC cells. The size of tumors varied from 2 mm to 120 mm.

The third group encompassed 9 tumors of higher stage with lymph node metastasis in 4 cases and distant metastasis in 4 cases. One tumor consisted of SE cells (Fig. 1e), 2 of the 9 cases consisted of ME cells (Fig. 1d) and finally 6 showed a mixture of distinct cells types including SB/ME or SE/ME cells or SE/LB or ME/LE cellular characteristics. Four tumors were Grade 2 and 5 cases Grade 3. The size of tumors varied between 25 mm and 160 mm. Seven of the nine patients died because of tumor progression within 3 years. The only patient with a SE cell-type tumor (pT1, N0, M1, G2) of this group (Fig. 1e) died because of metastatic disease after 1 year of the nephrectomy. One of the tumors (Supp. Info. Table I, Case 15) composed of small, medium and large size cells. Of interest, in this case the small eosinophilic part of the tumor has metastasized to the lymph node (Fig. 1f). All the four cases with large cells alone or combination of ME cells showed a deadly progression.

Gain of chromosome 1q is associated with fatal progression of papillary RCC

All patients from the first group and all but one from the second group were alive at the time of the last control. In contrary, 7 of the 9 patients in the third group died because of the metastatic disease. Five of the seven patients with duplication of chromosome 1q in the third group died because of disease within 4 months to 3 years after surgery. Further chromosomal changes occurred also exclusively in this group, namely -6q, -9p, -14q and some other losses. The Kaplan-Meier analysis showed a significantly decreased survival probability for patients having a tumor with duplications of 1q (Fig. 3). To identify the smallest overlapping duplication, we applied the full tiling path BAC-CGH to 20 papillary RCTs including 14 cases which were analyzed for global gene expression by the Affymetrix array. We confirmed the duplication of chromosome 1q and also deletion of chromosome 1p. Examples of the profiles are shown in Figure 2. Smaller deletions occurring each in 3 cases marked 2 target regions of deletions at p36.33-p36.31 and p36.11-p34.3, whereas gains at q21.3-q23.3 and q31.3-q32.1, each occurring in one case may mark the smallest gains at chromosome 1q in papillary RCCs.

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Figure 3. Kaplan-Meier survival probability analysis for 55 tumors without and with chromosome 1q duplication as listed in the Supporting Information Table I.

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Expression signature at chromosome 1q

To find the genes specifically overexpressed at the duplicated chromosome 1q, we compared the expression of genes from the chromosome 1q21.2-qter region between tumors with fatal progression and without progression by GSEA analysis. The heat map showed the enrichment of 50 genes associated with the tumor progression at chromosome 1q21-q23 region. We have selected 11 genes including PRCC gene (associated with the X; 1 translocation in rare occurring papillary RCTs) for real time RT-PCR analysis (Table II). None of the genes showed a significant difference in expression between the group of papillary RCCs without and with progression. We also selected 5 genes from the chromosome 1q31-q32 region. Both KIF14 and NEK2 were overexpressed in 4 of the 6 highly malignant papillary RCCs with chromosome 1q duplication (Fig. 4). However, some of tumors without progression showed also increased expression of both genes.

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Figure 4. Quantitative RT-PCR analysis of NEK2 and KIF14 in papillary RCCs without progression1–9 and with deadly progression.10–16 Cases with duplication of chromosome 1q are marked by stars.

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Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

In this study, we have separated 3 genetically well defined developmental stages of papillary RCTs. In contrast to the overlapping phenotype including the size, grade and cell-type of tumors, these genetic alterations mark unequivocally each step of tumor development. Our previous studies using karyotyping and microsatellite analysis proposed a 2 step clonal evolution of karyotype changes for papillary RCTs.8 We added now the third step of the clonal changes marking the fatal outcome of the disease. Of interest, duplication of chromosome 1q region was one of the first recurrent chromosomal changes detected in hematological and solid tumors nearly 30 years ago.20–23 Recently, several studies focused on the role of this genetic change in the tumor progression.24–29

The region of duplication at 1q22-q23.1 found in a papillary RCCs has also been identified in Wilms' tumor previously.26, 27 By expression analysis of the genes mapped to this chromosomal region, we were not able to find gene alterations associated with the progression of papillary RCCs. The other gain at 1q31.3-q32.1 chromosomal region has also been described in several other types of cancer and the KIF14 and NEK2 were suggested to be the target of duplication.27 Both genes were overexpressed preferentially in papillary RCCs with deadly outcome and duplication of chromosome 1q. We suggest that duplication of chromosome 1q as well as loss of chromosome 6q, 9p and 14q and also overexpression of KIF14 and NEK2 can be used for estimation of papillary RCC progression irrespective to the cell-type. Similar results regarding progression associated chromosomal changes such as 1q duplication and loss of chromosome 8 and 9 were also published in a large comprehensive study using classical karyotyping.30

We showed in this study that in contrary to the cellular characteristics the genetic alterations separate clearly 3 groups of tumors with distinct biological behavior. There is no doubt that small cell papillary RCTs of only 2–10 mm in diameter showing nuclear Grade 1 are benign tumors, e.g., papillary RCAs and papillary RCTs consisting of large eosinophilic cells displaying nuclear Grade 3 are papillary RCCs with high metastatic potential. However, a large number of papillary RCTs belongs to a gray zone between both ends of the morphological spectrum making it impossible to estimate the progression of the disease. We were not able to divide our cases into groups of so-called cellular Type 1 and 2 tumors as proposed by Delahunt and Eble.31 The papillary RCTs in our series displayed a continuous cellular differentiation from the small blastem-like cells towards large epithelial cells without any gap. Different level of epithelial differentiation was also found within a single tumor in a form of mixed cellular characteristics. Moreover, medium sized cells or mixed cell types may occur among papillary RCCs with and without fatal outcome.

Papillary RCTs share several morphological and genetic characteristics with Wilms' tumors. The link between embryonic rests and Wilms' tumor is well documented.32 Trisomies of chromosomes 7, 8, 12, 17 and 20, which are specific alterations in papillary RCTs, have also been found in 20% to 38% of Wilms' tumors.33 Recently, it was shown that duplication of chromosome 1q is associated with the poor prognosis of Wilms' tumor.24, 29 We have also showed a strong association between the presence of embryonic rest-like structures and papillary RCTs and suggested that papillary RCTs arise from not fully differentiated blastemal cells.1, 10, 11 We hypothesized that if such lesions persist and acquire trisomies of chromosomes 7 and 17, a papillary RCA will develop (Fig. 5). Additional changes such as gain of chromosome 3q, 8q, 12q, 16q and 20 might be important for shifting the biological behavior towards papillary RCC. And finally, as we showed in this study, an aggressive clinical behavior and deadly progression is associated with gain of chromosome 1q and also with the loss of chromosomes 6q, 9p and 14q. As the cellular phenotype of papillary RCTs is variable from case to case and also within a given tumor, the genetic classification of papillary RCA and papillary RCC without and with progression offer a better system to characterize the tumor biology of clinical significance.

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Figure 5. Proposed genetic/biological stages of the development of papillary RCTs.

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Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

The authors thank Drs. R. Kuiper and A. Geurts van Kessel for providing full tiling path BAC-arrays and sharing the cost of chemicals and Mrs E.J. Kamping for her technical expertise in the array hybridization (Participating investigators, Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands).

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
IJC_24180_sm_supptable1.doc133KSupporting Table 1. Pertinent clinicopathological and genetic data of 60 papillary renal cell tumors.

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