Gyula Kovacs

University of Pécs, Fuenfkirchen, Baranya, Hungary

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Publications (88)416.47 Total impact

  • Anetta Nagy · Daniel Banyai · David Semjen · Tamas Beothe · Gyula Kovacs ·
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    ABSTRACT: There are no adequate immunohistochemical markers for papillary renal cell tumours. The aim of this study was to establish a gene expression profile of papillary renal cell tumours using an expression microarray approach. Through hierarchical clustering and significant analysis of microarrays, we have selected the best 13 genes and analysed their expression by real-time polymerase chain reaction (RT-PCR). Of these genes, we selected SCEL as potential marker of interest. Immunohistochemical staining of tissue microarrays containing all major types of kidney cancers revealed positive staining for sciellin in 87 of 114 papillary renal cell tumours and in 13 of 19 precursor lesions. No other renal tumour types were positive for sciellin. Our study indicates that although not all tumours express sciellin, its expression may help to confirm the diagnosis papillary renal cell tumour.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2015; DOI:10.1007/s00428-015-1856-y · 2.65 Impact Factor
  • Tamas Beothe · Dmitry Zubakov · Gyula Kovacs ·
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    ABSTRACT: Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. . Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Genetics 05/2015; 208(9). DOI:10.1016/j.cancergen.2015.05.029 · 2.98 Impact Factor
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    ABSTRACT: Background: Androgen receptor (AR)-gene amplification, found in 20–30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. Methods: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. Results: Both high level gain in chromosome X (⩾4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (⩽600 nm, ⩽1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. Conclusion: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.
    British Journal of Cancer 01/2014; 110(6). DOI:10.1038/bjc.2014.13 · 4.84 Impact Factor
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  • Adrianna Szponar · Gyula Kovacs ·
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    ABSTRACT: Wilms' tumours (WT) and adult papillary renal cell tumours (pRCT) are associated with precursor lesions of embryonic origin. The aim of this study was to analyse the expression of WT1, KRT7, KRT8, KRT18 and KRT19 genes by immunohistochemistry in 74 precursor lesions associated with WTs, pRCTs and mucinous tubular and spindle cell carcinomas (MTSCC). All precursor lesions associated with Wilms' tumours were positive for WT1, whereas all precursor lesions in pRCT and MTSCC-bearing kidneys were negative. None of the WT-associated lesions were positive for KRT7, but 69-80% of lesions associated with pRCTs and MTSCCs were positive for KRT7. KRT8, KRT18 and KRT19 were found to be expressed in 80-100% of all types of precursor lesions. Our findings indicate that the precursor lesions analysed in this study are committed in an early stage of cellular differentiation to the development of either Wilms' tumours or papillary RCTs and MTSCCs.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2012; 460(4):423-7. DOI:10.1007/s00428-012-1209-z · 2.65 Impact Factor
  • Tamas Beothe · Anetta Nagy · Laszlo Farkas · Gyula Kovacs ·
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    ABSTRACT: Mutation of the p53 gene has been implicated in the development of carcinoma in situ (CIS) to invasive solid urothelial carcinomas (UC) whereas loss of heterozygosity (LOH) at chromosome 9 has been suggested to plag part in the development of papillary UCs. The p53 mutation and LOH at chromosomes 17p13.1 and 9 were analysed in 120 UCs. Tumor and matched normal DNA were used for microsatellite allelotyping of chromosome 17p and the entire chromosome 9. LOH at 17p13.1 was found in each grade and stage of the UCs, but mutation of the p53 occurred only in the highly malignant G3 tumors including papillary pT1G3 UCs. LOH were found at one or more of the seven tumor suppressor gene loci along chromosome 9 in all but two of the UCs with p53 mutation. Mutation of the p53 gene is not a pathway correlated genetic change, but is associated with the increased cell proliferation of G3 UCs.
    Anticancer research 02/2012; 32(2):523-7. · 1.83 Impact Factor
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    ABSTRACT: Papillary renal cell tumours (RCT) are characterized by specific trisomies. The aim of this study was to identify small regions of duplication marking putative tumour genes. Full-tiling path bacterial artificial chromosome (BAC) array hybridization of 20 papillary RCTs confirmed the duplication of chromosomes 7 and 17 and also displayed smaller regions of gains/amplifications of 1.3-13.1 Mb in size. Detailed analysis showed a microamplification of BAC clones containing the MET at the 7q31.2 and also amplification of a DNA segment harbouring the transcription factor hepatocyte nuclear factor 1 beta (HNF1B) at chromosome 17q12. Nuclear expression of HNF1B protein was detected in 38 of 67 papillary RCTs, in five of five mucinous tubular and spindle cell carcinomas (MTSCC) and five of five metanephric adenomas by immunohistochemistry. Moreover, nine nephrogenic rests containing tubular differentiated structures and all 14 and five precursor lesions associated with papillary RCTs and MTSCCs, respectively, showed strong nuclear positivity when compared to the expression level in proximal tubules of the corresponding normal kidney. Our findings indicate a role of HNF1B in association with the high frequency of chromosome 17q duplication in the development of papillary RCTs and MTSCCs as well as in their precursor lesions.
    Histopathology 03/2011; 58(6):934-43. DOI:10.1111/j.1365-2559.2011.03795.x · 3.45 Impact Factor

  • Cancer Research 01/2011; 70(8 Supplement):662-662. DOI:10.1158/1538-7445.AM10-662 · 9.33 Impact Factor
  • Ying Chen · Maria V Yusenko · Gyula Kovacs ·
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    ABSTRACT: The mortality of patients with conventional renal cell carcinomas (RCC) correlates directly with the development of metastasis, which cannot be reliably predicted simply by TNM classification. The aim of this study was to identify genes associated with the tumour progression. We have analysed the global gene expression in conventional RCCs, including those with and without progression by Affymetrix GeneChip and selected the genes by gene set enrichment analysis. The expression and function of KISS1R was validated by RT-PCR, western blotting and immunohistochemistry and by in vitro experiments. An immunohistochemical and clinical follow-up study showed that lack of KISS1R expression is associated with rapid progression of tumours. In vitro studies showed that activation of KISS1/KISS1R signalling by kisspeptin treatment decreases the motility and invasive capacity of tumour cells. The kisspeptin treatment also induces the expression of KISS1R in tumour cells in vitro and activates signalling in cases without constitutional expression of the receptor. Expression of the KISS1R protein can be used for estimating the prognosis of conventional RCCs. Confirming the activation of KISS1R signalling in vivo may open a way for kisspeptin treatment of patients with conventional RCCs.
    The Journal of Pathology 01/2011; 223(1):46-53. DOI:10.1002/path.2764 · 7.43 Impact Factor
  • Eva Kuntz · Maria V Yusenko · Anetta Nagy · Gyula Kovacs ·
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    ABSTRACT: Renal cell carcinoma occurs at higher frequency in acquired cystic renal disease than in the general population. We have analyzed 4 tumors obtained from the kidneys of 2 patients with acquired cystic renal disease, including 2 conventional renal cell carcinomas and 2 acquired cystic renal disease-associated tumors, for genetic alterations. DNA changes were established by applying the 44K Agilent Oligonucleotide Array-Based CGH (Agilent Technologies, Waldbronn, Germany), and mutation of VHL gene was detected by direct sequencing of the tumor genome. DNA losses and mutation of the VHL gene, which are characteristic for conventional renal cell carcinomas, were seen in 2 of the tumors. The acquired cystic renal disease-associated eosinophilic-vacuolated cell tumor showed gain of chromosomes 3 and 16. No DNA alterations occurred in the papillary clear cell tumor. We suggest that not only the morphology but also the genetics of renal cell tumors associated with acquired cystic renal disease may differ from those occurring in the general population.
    Human pathology 09/2010; 41(9):1345-9. DOI:10.1016/j.humpath.2009.09.022 · 2.77 Impact Factor
  • Maria V Yusenko · Anetta Nagy · Gyula Kovacs ·
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    ABSTRACT: We describe the molecular analysis of chromosomal rearrangements in familial t(3;6)(p12.3;q24.3) and t(3;12)(q13.13;q24.23) associated with the development of conventional renal cell carcinomas (RCC). We mapped the breakpoints by high-density oligo array comparative genomic hybridization of tumor cells in t(3;6) at chromosome 3p12.3 between PDZRN3 and CNTN3; the chromosomal rearrangement at 6q24.3 was mapped within the seventh intron of the STXBP5 gene. In the second case, the break at 3q13.13 was mapped downstream of PVRL3 and the breakpoint at 12q24.23 between HSPB8 and CCDC60, one allele of the latter being deleted. Reverse transcriptase polymerase chain reaction analysis of the PDZRN3, CNTN3, STXBP5, PVRL3, HSPB8, and CCDC60 genes revealed slight variation in the copy number of transcripts, but without correlation to the chromosomal rearrangements in translocation-associated and sporadic conventional RCCs. Loss of heterozygosity at chromosome 3p and mutation of VHL occurred at the same frequency in both familial and sporadic cases. Based on our model of nonhomologous chromatid exchange and the data on molecular studies, we suggest that the germline translocation serves as a rate-limiting step toward tumor development by generating a high number of cells with loss of the derivative chromosome carrying the 3p segment.
    Cancer genetics and cytogenetics 08/2010; 201(1):15-23. DOI:10.1016/j.cancergencyto.2010.04.018 · 1.93 Impact Factor
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    Maria V Yusenko · Thomas Ruppert · Gyula Kovacs ·
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    ABSTRACT: Renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) display morphological and functional alterations of the mitochondria. Previous studies showed that accumulation of mitochondria in ROs is associated with somatic mutations of mitochondrial DNA (mtDNA) resulting in decreased activity of the respiratory chain complex I, whereas in chromophobe RCC only heteroplasmic mtDNA mutations were found. To identify proteins associated with these changes, for the first time we have compared the mitochondrial proteomes of mitochondria isolated from ROs and chromophobe RCCs as well as from normal kidney tissues by two-dimensional polyacrylamide gel electrophoresis. The proteome profiles were reproducible within the same group of tissues in subsequent experiments. The expression patterns within each group of samples were compared and 81 in-gel digested spots were subjected to nanoLC-MS/MS-based identification of proteins. Although the list of mitochondrial proteins identified in this study is incomplete, we identified the downregulation of NDUFS3 from complex I of the respiratory chain and upregulation of COX5A, COX5B, and ATP5H from complex IV and V in ROs. In chromophobe RCCs downregulation of ATP5A1, the alpha subunit of complex V, has been observed, but no changes in expression of other complexes of the respiratory chain were detected. To confirm the role of respiratory chain complex alterations in the morphological and/or functional changes in chromophobe RCCs and ROs, further studies will be necessary.
    International journal of biological sciences 04/2010; 6(3):213-24. · 4.51 Impact Factor
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    ABSTRACT: The discovery of ERG/ETV1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV1 gene rearrangements and PTEN gene loss status. We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data. ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a 'good prognosis' population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the 'good prognosis' group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved. Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management.
    British Journal of Cancer 02/2010; 102(4):678-84. DOI:10.1038/sj.bjc.6605554 · 4.84 Impact Factor
  • Adrianna Szponar · Tamas Beothe · Gyula Kovacs ·

    Histopathology 01/2010; 56(2):263-5. DOI:10.1111/j.1365-2559.2009.03472.x · 3.45 Impact Factor
  • Adrianna Szponar · Maria V Yusenko · Gyula Kovacs ·
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    ABSTRACT: Previous karyotyping and fluorescence in situ hybridization analysis of metanephric adenomas (MAs) has yielded controversial data. The aim of this study was to detect small genomic alterations, if any, specific to MAs by applying high-resolution oligoarrays. DNA extracted from paraffin blocks of six metanephric adenomas was hybridized onto Agilent oligoarrays with approximately 43,000 in situ synthesized 60-mer oligonucleotide probes that span coding and non-coding sequences with an average spatial resolution of approximately 35 kb. None of the metanephric adenomas showed DNA copy number changes. To confirm our results, DNA extracted from the paraffin block of a chromophobe renal cell carcinoma (RCC) was simultaneously hybridized to one of the four arrays on the same slides as an internal control. The chromophobe RCC showed loss of several chromosomes but no alteration was seen in MAs. We have confirmed the negative results by dye-swap and sex mismatch hybridization experiments. Our high-resolution oligoarray analysis indicates that metanephric adenomas lack DNA copy number alterations. This finding may help to differentiate between metanephric adenomas from Wilms' tumour and papillary renal cell adenoma with overlapping phenotype.
    Histopathology 01/2010; 56(2):212-6. DOI:10.1111/j.1365-2559.2009.03473.x · 3.45 Impact Factor
  • Maria V Yusenko · Gyula Kovacs ·
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    ABSTRACT: The variation in cytoplasmic staining and growth pattern makes differential diagnosis of chromophobe renal cell carcinoma (RCC), especially from renal oncocytomas (RO), uncertain. The aim was to find an immunohistochemical marker to improve the diagnosis of chromophobe RCC. The expression profile of renal cell tumours was established using the Affymetrix HG U133 Plus 2.0 microarray. After performing hierarchical clustering we selected the best 50 genes and analysed 24 of them by reverse transcriptase-polymerase chain reaction. TMC5, RBM35, SPINK7, CD82/KAI1 and GLIS3 were expressed specifically in chromophobe RCCs. Immunohistochemical studies confirmed the specificity of CD82/KAI1. Analysis of tissue microarrays containing all major types of renal neoplasm revealed immunopositivity for CD82/KAI1 in 78% (69/88) of chromophobe RCCs but in only 3% (6/220) of conventional or clear cell RCCs. All 90 ROs and 171 papillary RCCs were immunonegative for CD82/KAI1. To confirm the specificity of antibody by immunoblotting, we transfected HEK293 cells with an expression vector containing the full-length CD82/KAI1. CD82/KAI1 is an excellent marker for distinguishing chromophobe RCCs from other types of renal cell tumours, especially from ROs with overlapping phenotype.
    Histopathology 12/2009; 55(6):687-95. DOI:10.1111/j.1365-2559.2009.03449.x · 3.45 Impact Factor
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    Claudia Paret · Zorica Schön · Adrianna Szponar · Gyula Kovacs ·
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    ABSTRACT: Conventional renal cell carcinoma (RCC) is the most common renal cancer. As the metastatic conventional RCC is practically incurable, there is a need for markers to estimate the tumour aggressiveness. To identify and characterise new marker(s) associated with the poor prognosis of conventional RCC. RNA from 24 conventional RCCs was analysed for global gene expression by Affymetrix U133 Plus 2.0 arrays. Tissue microarrays containing 224 renal tumours including 87 conventional RCCs were used for immunohistochemistry. Cell lines HD2, HD48, HA344 and HA465 established in our laboratory were used for invasion assay and zymography. Serum amyloid A 1 (SAA1) was found to be upregulated in conventional RCCs and it has been analysed by quantitative RT-PCR and immunohistochemistry on TMAs to establish the correlation between SAA1 protein expression and patient survival by uni and multivariate analysis. The effect of SAA1 on tumour cell behaviour in vitro has also been examined by invasion assay and zymography. SAA1 RNA is expressed in conventional RCC samples of patients with poor prognosis. Immunohistochemistry of 72 conventional RCCs with a 5 yr follow up showed a correlation between SAA1 expression and the clinical outcome of disease. Stimulation of conventional RCC cell lines with recombinant SAA1 increased the expression of metalloproteinase (MMP)-9 and the invasive potential of tumour cells. Limitation of the study is a relatively small number (72) of patients having follow up. SAA1 seems to be a useful marker to estimate the prognosis of conventional RCCs.
    European Urology 08/2009; 57(5):859-66. DOI:10.1016/j.eururo.2009.08.014 · 13.94 Impact Factor
  • I Balint · A Szponar · A Jauch · G Kovacs ·
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    ABSTRACT: Papillary renal cell tumours (RCTs) have been described as a genetic entity. Recently, papillary RCTs have been divided into small (type 1) and large (type 2) cell tumours. Subsequent DNA analyses have resulted in controversial data regarding putative genetic changes marking type 1 and type 2 tumours. The aim of this study was to improve the original description that papillary RCT is a genetic entity regardless of the phenotypic variation. DNA from 163 papillary RCTs, including 82 multiplex tumours from eight hereditary cases, was analysed for copy number changes by chromosomal comparative genomic hybridisation (CGH) and/or for allelic changes at chromosomes 7 and 17 by microsatellite analysis. The results of the genetic analysis were compared with the cytological characteristics of the tumours. The results showed alterations of chromosomes 7 and 17 at similar frequencies in papillary RCTs with characteristics ranging from small to large cell, nuclear grade 1 to 3, and 3 mm to 16 cm diameter. Trisomies of chromosomes 7 and 17 are specific genetic alterations in papillary RCTs irrespective of their size, grade and cellular differentiation.
    Journal of clinical pathology 07/2009; 62(10):892-5. DOI:10.1136/jcp.2009.066423 · 2.92 Impact Factor

Publication Stats

4k Citations
416.47 Total Impact Points


  • 2004-2015
    • University of Pécs
      • Insititute of Laboratory Medicine
      Fuenfkirchen, Baranya, Hungary
  • 1997-2011
    • Universität Heidelberg
      • • Department of Molecular Oncology
      • • Department of Urology
      Heidelburg, Baden-Württemberg, Germany