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VHL-abhängige und unabhängige Mechanismen des Nierenzellkarzinoms. Ueberführung in klinische Anwendungen

English title VHL-dependent and independent mechanisms in human renal cell cancer and their translation into clinical applications
Applicant Moch Holger
Number 135792
Funding scheme Project funding (Div. I-III)
Research institution Institut für Klinische Pathologie Departement für Pathologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Clinical Cancer Research
Start/End 01.01.2012 - 31.12.2015
Approved amount 468'000.00
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Keywords (2)

Tissue; Serum

Lay Summary (German)

Lead
Lay summary

Das Nierenkarzinom ist ein Tumor mit häufiger Metastasierung. Während Chemo-und Radiotherapie zur Behandlung metastasierender Nierenkazinome selten Wirkung zeigen, werden seit einigen Jahren neue Therapien mit Antikörpern und kleinen Molekülen gegen spezifische Oberflächenrezeptoren eingesetzt. Der Einsatz dieser neuen Therapien erfordert in der Regel Biomarker-Analysen im Tumorgewebe. Im Gegensatz zu Mamma- und Lungenkarzinomen sind solche prädiktiven Biomarker beim Nierenkazinom nicht bekannt.

Im vorliegenden Projekt, werden bestimmte Mutationen eines wichtigen Nierenkarzinom-Gens (von Hippel-Lindau-Gen) untersucht, um ein Ansprechen auf solche Therapien vorhersagen zu können. Gleichzeitig wird ein Bluttest entwickelt, der möglicherweise das Auftreten von Metastasen nach der Entfernung des primären Nierentumors anzeigen könnte. Mit diesem kombinierten Ansatz versucht man, die Prognose des Nierenkarzinoms einserseits druch verbesserte Diagnostik, andererseits durch eine individualisierte Therapie zu verbessern. Dies erfolgt durch eine interdisziplinäre Zusammenarbeit von Pathologen, Molekularbiologen und Onkolgen.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma
Bihr Svenja, Ohashi Riuko, Moore Ariane L., Rüschoff Jan H., Beisel Christian, Hermanns Thomas, Mischo Axel, Corrò Claudia, Beyer Jörg, Beerenwinkel Niko, Moch Holger, Schraml Peter (2019), Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma, in Neoplasia, 21(2), 247-256.
Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: a non-existent or new tumour entity?
Batavia Aashil A, Schraml Peter, Moch Holger (2019), Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: a non-existent or new tumour entity?, in Histopathology, 74(1), 60-67.
VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma
Razafinjatovo Caroline Fanja, Stiehl Daniel, Deininger Eva, Rechsteiner Markus, Moch Holger, Schraml Peter (2017), VHL missense mutations in the p53 binding domain show different effects on p53 signaling and HIFα degradation in clear cell renal cell carcinoma, in Oncotarget, 8(6), 2.
Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance
Razafinjatovo Caroline, Bihr Svenja, Mischo Axel, Vogl Ursula, Schmidinger Manuela, Moch Holger, Schraml Peter (2016), Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance, in BMC Cancer, 16(1), 638-638.
Discretization of Gene Expression Data Unmasks Molecular Subgroups Recurring in Different Human Cancer Types
Beleut Manfred, Soeldner Robert, Egorov Mark, Guenther Rolf, Dehler Silvia, Morys-Wortmann Corinna, Moch Holger, Henco Karsten, Schraml Peter (2016), Discretization of Gene Expression Data Unmasks Molecular Subgroups Recurring in Different Human Cancer Types, in PLOS ONE, 11(8), e0161514-e0161514.
PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinomaPD-L1 is regulated by HIF in CCRCC
Ruf Melanie, Moch Holger, Schraml Peter (2016), PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinomaPD-L1 is regulated by HIF in CCRCC, in International Journal of Cancer, 139(2), 396-403.
A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization.
Nowicka AM, Häuselmann I, Borsig L, Bolduan S, Schindler M, Schraml P, Heikenwalder M, Moch H (2016), A novel pVHL-independent but NEMO-driven pathway in renal cancer promotes HIF stabilization., in Oncogene, 35(24), 25-38.
Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.
Schödel J, Grampp S, Maher ER, Moch H, Ratcliffe PJ, Russo P, Mole DR (2016), Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer., in European Urology, 69(4), 646-657.
PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma.
Ruf Melanie, Moch Holger, Schraml Peter (2016), PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma., in International Journal Cancer, 139, 396-403.
The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.
Moch Holger, Cubilla Antonio, Humphrey Peter, Reuter Victor, Ulbright Thomas (2016), The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours., in European Urology, 70, 93-105.
WHO Classification of Tumours of the Urinary System and Male Genital Organs
Moch Holger, Humphrey Peter, Ulbright Thomas, Reuter Victor (2016), WHO Classification of Tumours of the Urinary System and Male Genital Organs, IARC, Lyon.
Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer
Pflueger Dorothee, Mittmann Christiane, Dehler Silvia, Rubin Mark A, Moch Holger, Schraml Peter (2015), Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer, in BMC Genomics, 16(1), 247-247.
Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer
Pflueger Dorothee, Mittmann Christiane, Dehler Silvia, Rubin Mark A, Moch Holger, Schraml Peter (2015), Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer, in BMC Genomics, 16(1), 247-247.
pVHL/HIF-Regulated CD70 Expression Is Associated with Infiltration of CD27+ Lymphocytes and Increased Serum Levels of Soluble CD27 in Clear Cell Renal Cell Carcinoma
Ruf M., Mittmann C., Nowicka A. M., Hartmann A., Hermanns T., Poyet C., van den Broek M., Sulser T., Moch H., Schraml P. (2015), pVHL/HIF-Regulated CD70 Expression Is Associated with Infiltration of CD27+ Lymphocytes and Increased Serum Levels of Soluble CD27 in Clear Cell Renal Cell Carcinoma, in Clinical Cancer Research, 21(4), 889-898.
Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor: two variants of a morphologic, immunohistochemical, and genetic distinct entity of renal cell carcinoma.
Deml KF, Schildhaus HU, Compérat E, von Teichman A, Storz M, Schraml P, Bonventre JV, Fend F, Fleige B, Nerlich A, Gabbert HE, GaBler N, Grobholz R, Hailemariam S, Hinze R, Knüchel R, Lhermitte B, Nesi G, Rüdiger T, Sauter G, Moch H (2015), Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor: two variants of a morphologic, immunohistochemical, and genetic distinct entity of renal cell carcinoma., in American Journal Surgical Pathology, 39(7), 889-901.
Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer.
Pflueger D., Mittmann C., Dehler S., Rubin M. A., Moch H., Schraml P. (2015), Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer., in BMC Genomics, 16, 247.
Interaction of tumor cells with infiltrating lymphocytes via CD70 and CD27 in clear cell renal cell carcinoma.
Ruf Melanie, Moch Holger, Schraml Peter (2015), Interaction of tumor cells with infiltrating lymphocytes via CD70 and CD27 in clear cell renal cell carcinoma., in Oncoimmunology, 4(12), e1049805.
pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma.
Ruf M., Mittmann C., Nowicka A. M., Hartmann A., Hermanns T., Poyet C., van den Broek M., Sulser T., Moch H., Schraml P. (2015), pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma., in Clinical Cancer Research, 21(4), 889-898.
A clearer view of the molecular complexity of clear cell renal cell carcinoma.
Frew Ian, Moch Holger (2014), A clearer view of the molecular complexity of clear cell renal cell carcinoma., in Annual review of pathology, 10, 263-289.
Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression.
Wyler L., Napoli C. U., Ingold B., Sulser T., Heikenwalder M., Schraml P., Moch H. (2014), Brain metastasis in renal cancer patients: metastatic pattern, tumour-associated macrophages and chemokine/chemoreceptor expression., in British Journal of Cancer, 110(3), 686-694.
The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinomaPTPRJ in clear cell renal cell carcinoma
Casagrande Silvia, Ruf Melanie, Rechsteiner Markus, Morra Laura, Brun-Schmid Sonja, von Teichman Adriana, Krek Wilhelm, Schraml Peter, Moch Holger (2013), The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinomaPTPRJ in clear cell renal cell carcinoma, in The Journal of Pathology, 229(4), 525-534.
Loss of PBRM1 expression is associated with renal cell carcinoma progression
Pawłowski Rafal, Mühl Sarah M., Sulser Tullio, Krek Wilhelm, Moch Holger, Schraml Peter (2013), Loss of PBRM1 expression is associated with renal cell carcinoma progression, in International Journal of Cancer, 132(2), E11-E17.
An overview of renal cell cancer: pathology and genetics.
Moch H (2013), An overview of renal cell cancer: pathology and genetics., in Seminars in cancer biology, 23(1), 3-9.
Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing.
Pflueger D., Sboner A., Storz M., Roth J., Comperat E., Bruder E., Rubin M. A., Schraml P., Moch H. (2013), Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing., in Neoplasia, 15(11), 1231-1240.
Loss of PBRM1 expression is associated with renal cell carcinoma progression.
Pawlowski R., Muhl S. M., Sulser T., Krek W., Moch H., Schraml P. (2013), Loss of PBRM1 expression is associated with renal cell carcinoma progression., in International journal of cancer, 132(2), E11-7.
The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinoma.
Casagrande S., Ruf M., Rechsteiner M., Morra L., Brun-Schmid S., von Teichman A., Krek W., Schraml P., Moch H. (2013), The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinoma., in The Journal of pathology, 229(4), 525-534.
Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma.
Dannenmann S. R., Thielicke J., Stockli M., Matter C., von Boehmer L., Cecconi V., Hermanns T., Hefermehl L., Schraml P., Moch H., Knuth A., van den Broek M. (2013), Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma., in Oncoimmunology, 2(3), e23562.
αv-Integrin isoform expression in primary human tumors and brain metastases.
Vogetseder A., Thies S., Ingold B., Roth P., Weller M., Schraml P., Goodman S. L., Moch H. (2013), αv-Integrin isoform expression in primary human tumors and brain metastases., in International journal of cancer, 133(10), 2362-2371.
Identification and functional characterization of pVHL-dependent cell surface proteins in renal cell carcinoma.
Boysen G., Bausch-Fluck D., Thoma C. R., Nowicka A. M., Stiehl D. P., Cima I., Luu V. D., von Teichman A., Hermanns T., Sulser T., Ingold-Heppner B., Fankhauser N., Krek W., Schraml P, Wollscheid B, Moch H. (2012), Identification and functional characterization of pVHL-dependent cell surface proteins in renal cell carcinoma., in Neoplasia, 14(6), 535-546.
Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome.
Beleut M., Zimmermann P., Baudis M., Bruni N., Buhlmann P., Laule O., Luu V. D., Gruissem W., Schraml P, Moch H. (2012), Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome., in BMC Cancer, 12, 310.
Reliable detection of subclonal single-nucleotide variants in tumour cell populations.
Gerstung M, Beisel C, Rechsteiner M, Wild P, Schraml P, Moch H, Beerenwinkel N. (2012), Reliable detection of subclonal single-nucleotide variants in tumour cell populations., in Nat Commun, 3, 811.

Collaboration

Group / person Country
Types of collaboration
Rubin Group Cornell University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events



Self-organised

Title Date Place
WHO Symposium Recent Advances in Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs 14.08.2015 Zurich, Switzerland

Awards

Title Year
German Society of Pathology, Poster Price 2013

Associated projects

Number Title Start Funding scheme
118356 Uncovering the VHL-regulated proteome in human renal cell cancer - implications for renal cancer biology and therapy 01.10.2007 Project funding (Div. I-III)
166391 Tumor heterogeneity and cancer stem cell properties in renal cancer 01.06.2016 Project funding (Div. I-III)
118356 Uncovering the VHL-regulated proteome in human renal cell cancer - implications for renal cancer biology and therapy 01.10.2007 Project funding (Div. I-III)

Abstract

Renal cell carcinoma (RCC) is the most frequent malignant tumor affecting the adult kidney. The incidence of RCC is increasing in many western countries. To date, there is no chemotherapy for the treatment of advanced kidney cancer with objective response rates higher than 15%. Recently, antibodies and small molecules targeting VEGFR and mTOR (Avastin, Temsirolimus, Sunitinib, Sorafenib) showed promising effects in patients with metastatic RCC. However, these treatments have significant toxic side effects and response is only seen in a subgroup of renal cancer patients. To further succeed in the treatment of RCC and to improve the prognosis of RCC patients, development of a serum test for the detection of RCC metastases as well as the identification of predictive markers for treatment reponse are of utmost importance. The proposed project is a continuation of previous SNF grants, which allowed the identification of novel molecular mechanisms involved in renal cancer initiation and metastasis. Our novel project aims at at the translation of this knowledge into clinical practice. Loss of function of the von Hippel-Lindau (VHL) tumor suppressor due to mutation is characteristic for most cases of sporadic clear cell RCC (ccRCC). Work on the mechanism of action of the VHL product, pVHL, revealed that it is a multipurpose adapter protein involved in a variety of cellular processes including ubiquitin-mediated degradation of hypoxia-inducible factor ? (HIF?), stabilization and maintainance of primary cilia and promotion of proper spindle orientation and chromosomal stability. Loss of pVHL function leads to the deregulation of transcription regulatory pathways as well as of the cytoskeleton and the extracellular matrix, which play critical roles in cell cycle arrest, apoptosis, adhesion, metabolism, angiogenesis and metastasis. It has been shown that different VHL mutations trigger different signalling pathways. Moreover, in about 20% of ccRCC VHL is not affected suggesting the existence of other tumor suppressors whose loss of function leads to the same phenotypic output seen in VHL-dependent ccRCC. VHL-independent pathways have not yet been described. Detailed molecular understanding of the role of the pVHL-dependent and independent signaling circuitry in cancer will offer improved insights into the events leading to sporadic ccRCC. Hypothesis This proposal is based on the hypotheses 1) that it is possible to develop a VHL-dependent serum signature for clear cell renal cancer, which will facilitate early detection of RCC and RCC metastasis in the blood;2) that the VHL mutation type is relevant for the biological behaviour of clear cell RCC and potentially it’s response to targeted therapy;3) that the characterization of novel, VHL-independent mechanisms allows further subgrouping of clear cell RCC. The knowledge of these subgroups will help to better understand the biological processes implicated in RCC which in turn will lead to improved individualized treatment strategies. Specific AimsThe promising results of previous pilot projects led to the description of 3 specific research subprojects, which aims at:Part A)- the establishment of a RCC serum barcode based on the identified RCC cell surfaceome;- the functional analysis of cell surface glycoproteins for potential anti-tumor treatment.Part B)- the functional analysis of VHL mutations in RCC by focussing on their effects on pVHL/HIF? stability; - the correlation of the VHL mutation type with patient prognosis and response to targeted therapies.Part C)- the identification of VHL-independent molecular mechanisms in RCC, e.g. gene fusions, and transcriptional “chimerisms” in renal cancer using next-generation RNA sequencing;- the validation of novel gene fusions and read through events by Q-PCR and FISH;- the evaluation of the frequency of these events on tissue microarrays (TMA) with more than 1000 primary RCC and more than 100 renal carcinoma metastases.
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