TY - JOUR
A1 - Schmitt, Jana
A1 - Backes, Christina
A1 - Nourkami-Tutdibi, Nasenien
A1 - Leidinger, Petra
A1 - Deutscher, Stephanie
A1 - Beier, Markus
A1 - Gessler, Manfred
A1 - Graf, Norbert
A1 - Lenhof, Hans-Peter
A1 - Keller, Andreas
A1 - Meese, Eckart
T1 - Treatment-independent miRNA signature in blood of wilms tumor patients
JF - BMC Genomics
N2 - Background
Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001.
Results
We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls.
Conclusion
Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment.
KW - miRNA
Y1 - 2012
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124034
VL - 13
IS - 379
ER -
TY - JOUR
A1 - Wegert, Jenny
A1 - Vokuh, Christian
A1 - Ziegler, Barbara
A1 - Ernestus, Karen
A1 - Leuschner, Ivo
A1 - Furtwängler, Rhoikos
A1 - Graf, Norbert
A1 - Gessler, Manfred
T1 - TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia
JF - The Journal of Pathology: Clinical Research
N2 - TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87%), but this rate dropped to 26% for stages II–IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.
KW - tumour heterogeneity
KW - Wilms tumour
KW - nephroblastoma
KW - anaplasia
KW - TP53
Y1 - 2017
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158302
VL - 3
ER -
TY - JOUR
A1 - Vujanić, Gordan M.
A1 - Gessler, Manfred
A1 - Ooms, Ariadne H. A. G.
A1 - Collini, Paola
A1 - Coulomb-l'Hermine, Aurore
A1 - D'Hooghe, Ellen
A1 - de Krijger, Ronald R.
A1 - Perotti, Daniela
A1 - Pritchard-Jones, Kathy
A1 - Vokuhl, Christian
A1 - van den Heuvel-Eibrink, Marry M.
A1 - Graf, Norbert
T1 - The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol
JF - Nature Reviews Urology
N2 - On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel.
KW - molecular biology
KW - paediatric cancer
KW - pathology
KW - renal cancer
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233265
VL - 15
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Grupe, Andrew
A1 - Grzeschik, Karl-Heinz
A1 - Pongs, Olaf
T1 - The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene
N2 - Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the firsthuman cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-pl4, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14, 200-600 kb telomeric to the FSHB gene.
KW - Biochemie
Y1 - 1992
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59184
ER -
TY - JOUR
A1 - Gröbner, Susanne N.
A1 - Worst, Barbara C.
A1 - Weischenfeldt, Joachim
A1 - Buchhalter, Ivo
A1 - Kleinheinz, Kortine
A1 - Rudneva, Vasilisa A.
A1 - Johann, Pascal D.
A1 - Balasubramanian, Gnana Prakash
A1 - Segura-Wang, Maia
A1 - Brabetz, Sebastian
A1 - Bender, Sebastian
A1 - Hutter, Barbara
A1 - Sturm, Dominik
A1 - Pfaff, Elke
A1 - Hübschmann, Daniel
A1 - Zipprich, Gideon
A1 - Heinold, Michael
A1 - Eils, Jürgen
A1 - Lawerenz, Christian
A1 - Erkek, Serap
A1 - Lambo, Sander
A1 - Waszak, Sebastian
A1 - Blattmann, Claudia
A1 - Borkhardt, Arndt
A1 - Kuhlen, Michaela
A1 - Eggert, Angelika
A1 - Fulda, Simone
A1 - Gessler, Manfred
A1 - Wegert, Jenny
A1 - Kappler, Roland
A1 - Baumhoer, Daniel
A1 - Stefan, Burdach
A1 - Kirschner-Schwabe, Renate
A1 - Kontny, Udo
A1 - Kulozik, Andreas E.
A1 - Lohmann, Dietmar
A1 - Hettmer, Simone
A1 - Eckert, Cornelia
A1 - Bielack, Stefan
A1 - Nathrath, Michaela
A1 - Niemeyer, Charlotte
A1 - Richter, Günther H.
A1 - Schulte, Johannes
A1 - Siebert, Reiner
A1 - Westermann, Frank
A1 - Molenaar, Jan J.
A1 - Vassal, Gilles
A1 - Witt, Hendrik
A1 - Burkhardt, Birgit
A1 - Kratz, Christian P.
A1 - Witt, Olaf
A1 - van Tilburg, Cornelis M.
A1 - Kramm, Christof M.
A1 - Fleischhack, Gudrun
A1 - Dirksen, Uta
A1 - Rutkowski, Stefan
A1 - Frühwald, Michael
A1 - Hoff, Katja von
A1 - Wolf, Stephan
A1 - Klingebeil, Thomas
A1 - Koscielniak, Ewa
A1 - Landgraf, Pablo
A1 - Koster, Jan
A1 - Resnick, Adam C.
A1 - Zhang, Jinghui
A1 - Liu, Yanling
A1 - Zhou, Xin
A1 - Waanders, Angela J.
A1 - Zwijnenburg, Danny A.
A1 - Raman, Pichai
A1 - Brors, Benedikt
A1 - Weber, Ursula D.
A1 - Northcott, Paul A.
A1 - Pajtler, Kristian W.
A1 - Kool, Marcel
A1 - Piro, Rosario M.
A1 - Korbel, Jan O.
A1 - Schlesner, Matthias
A1 - Eils, Roland
A1 - Jones, David T. W.
A1 - Lichter, Peter
A1 - Chavez, Lukas
A1 - Zapatka, Marc
A1 - Pfister, Stefan M.
T1 - The landscape of genomic alterations across childhood cancers
JF - Nature
N2 - Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
KW - cancer genomics
KW - oncogenesis
KW - paediatric cancer
KW - predictive markers
KW - translational research
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229579
VL - 555
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Hameister, H.
A1 - Henry, I.
A1 - Junien, C.
A1 - Braun, T.
A1 - Arnold, H. H.
T1 - The human MyoD1 (MYF3) gene maps on the short arm of chromosome 11 but is not associated with the WAGR locus or the region for the Beckwith-Wiedemann syndrome
N2 - The human gene encoding the myogenic determination factor myf3 (mouse MyoD1) has been mapped to the short arm of chromosome 11. Analysis of several somatic cell hybrids containing various derivatives with deletions or translocations revealed that the human MyoD (MYF3) gene is not associated with the WAGR locus at chromosomal band 11pl3 nor with the loss of the heterozygosity region at 11p15.5 related to the Beckwith-Wiedemann syndrome. Subregional mapping by in situ hybridization with an myf3 specific probe shows that the gene resides at the chromosomal band llp14, possibly at llp14.3.
KW - Biochemie
Y1 - 1990
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59221
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - König, A.
A1 - Bruns, G. A. P.
T1 - The genomic organization and expression of the WT1 gene
N2 - The Wilms tumor gene WTl, a proposed tumor suppressor gene, has been identifled based on its location within a homozygous deletion found in tumor tissue. The gene encodes a putative transcription factor containing a Cys/His zinc finger domain. The critical homozygous deletions, however, are rarely seen, suggesting that in many cases the gene may be inactivated by more subtle alterations. To facilitate the seareh for smaller deletions and point mutations we have established the genomic organization of the WTl gene and have determined the sequence of all 10 exons and flanking intron DNA. The pattern of alternative splicing in two regions has been characterized in detail. These results will form the basis for future studies of mutant alleles at this locus.
KW - Biochemie
Y1 - 1992
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59195
ER -
TY - JOUR
A1 - Heisig, Julia
A1 - Weber, David
A1 - Englberger, Eva
A1 - Winkler, Anja
A1 - Kneitz, Susanne
A1 - Sung, Wing-Kin
A1 - Wolf, Elmar
A1 - Eilers, Martin
A1 - Wei, Chia-Lin
A1 - Gessler, Manfred
T1 - Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors
N2 - HEY bHLH transcription factors have been shown to regulate multiple key steps in cardiovascular development. They can be induced by activated NOTCH receptors, but other upstream stimuli mediated by TGFß and BMP receptors may elicit a similar response. While the basic and helix-loop-helix domains exhibit strong similarity, large parts of the proteins are still unique and may serve divergent functions. The striking overlap of cardiac defects in HEY2 and combined HEY1/HEYL knockout mice suggested that all three HEY genes fulfill overlapping function in target cells. We therefore sought to identify target genes for HEY proteins by microarray expression and ChIPseq analyses in HEK293 cells, cardiomyocytes, and murine hearts. HEY proteins were found to modulate expression of their target gene to a rather limited extent, but with striking functional interchangeability between HEY factors. Chromatin immunoprecipitation revealed a much greater number of potential binding sites that again largely overlap between HEY factors. Binding sites are clustered in the proximal promoter region especially of transcriptional regulators or developmental control genes. Multiple lines of evidence suggest that HEY proteins primarily act as direct transcriptional repressors, while gene activation seems to be due to secondary or indirect effects. Mutagenesis of putative DNA binding residues supports the notion of direct DNA binding. While class B E-box sequences (CACGYG) clearly represent preferred target sequences, there must be additional and more loosely defined modes of DNA binding since many of the target promoters that are efficiently bound by HEY proteins do not contain an Ebox motif. These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression.
KW - Biologie
Y1 - 2012
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75341
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Bruns, Gail A.
T1 - Sequence of the WT1 upstream region including the Wit-1 gene
N2 - No abstract available
Y1 - 1993
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30193
ER -
TY - JOUR
A1 - van Heyningen, V.
A1 - Bickmore, W. A.
A1 - Seawright, A.
A1 - Fletcher, J. M.
A1 - Maule, J.
A1 - Fekete, G.
A1 - Gessler, Manfred
A1 - Bruns, G. A.
A1 - Huerre-Jeanpierre, C.
A1 - Junien, C.
T1 - Role for the Wilms tumor gene in genital development?
N2 - No abstract available
KW - Biochemie
Y1 - 1990
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59238
ER -
TY - JOUR
A1 - Wegert, Jenny
A1 - Bausenwein, Sabrina
A1 - Kneitz, Susanne
A1 - Roth, Sabine
A1 - Graf, Norbert
A1 - Geissinger, Eva
A1 - Gessler, Manfred
T1 - Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro
N2 - Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.
KW - Krebs
KW - Wilms tumor
KW - nephroblastoma
KW - primary tumor cell culture
KW - tumor model
KW - retinoic acid
Y1 - 2011
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69137
ER -
TY - JOUR
A1 - Wegert, Jenny
A1 - Vokuhl, Christian
A1 - Collord, Grace
A1 - Del Castillo Velasco-Herrera, Martin
A1 - Farndon, Sarah J.
A1 - Guzzo, Charlotte
A1 - Jorgensen, Mette
A1 - Anderson, John
A1 - Slater, Olga
A1 - Duncan, Catriona
A1 - Bausenwein, Sabrina
A1 - Streitenberger, Heike
A1 - Ziegler, Barbara
A1 - Furtwängler, Rhoikos
A1 - Graf, Norbert
A1 - Stratton, Michael R.
A1 - Campbell, Peter J.
A1 - Jones, David TW
A1 - Koelsche, Christian
A1 - Pfister, Stefan M.
A1 - Mifsud, William
A1 - Sebire, Neil
A1 - Sparber-Sauer, Monika
A1 - Koscielniak, Ewa
A1 - Rosenwald, Andreas
A1 - Gessler, Manfred
A1 - Behjati, Sam
T1 - Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants
JF - Nature Communications
N2 - Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.
KW - cancer
KW - genetics
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233446
VL - 9
ER -
TY - JOUR
A1 - Tu, Xiaolin
A1 - Chen, Jianquan
A1 - Lim, Joohyun
A1 - Karner, Courtney M.
A1 - Lee, Seung-Yon
A1 - Heisig, Julia
A1 - Wiese, Cornelia
A1 - Surendran, Kameswaran
A1 - Kopan, Raphael
A1 - Gessler, Manfred
A1 - Long, Fanxin
T1 - Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1
JF - PLoS Genetics
N2 - Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.
KW - expression
KW - axial skeletal defects
KW - transcription factor
KW - alagille syndrome
KW - osteoblast differentiation
KW - human jagged1
KW - aortic-valve
KW - T cells
KW - mutations
KW - mice
Y1 - 2012
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133490
VL - 8
IS - 3
ER -
TY - JOUR
A1 - Henry, Isabelle
A1 - Hoovers, Jan
A1 - Barichard, Fernande
A1 - Berthéas, Marie-Francoise
A1 - Puech, Anne
A1 - Prieur, Fabienne
A1 - Gessler, Manfred
A1 - Bruns, Gail
A1 - Mannens, Marcel
A1 - Junien, Claudine
T1 - Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family
N2 - The combined use of qualitative and quantitative analysis of I I p I 3 polymorphic markers tagether with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to I I p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible (or recurrence of del( I I )(p 13p 14) in the family: an insertion of band I I p 13-p 14 carrying the genes for predisposition to Wilms' tumor, WT I, and for aniridia, AN2, into the long arm of chromosome I I in II q 13-q 1<4. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del( II )(p 13). Two of these women gave birth to children carrying a deleted chromosome II. most likely resulting from the loss of the I I p 13 band inserted in I I q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide Variation in clinical expression. One child, with the karyotype 46,XY,del(ll)(pllpl4), presented the full-blown WAGR syndrome with anlridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del( I I )(p I 3), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WTI gene can result in similar genital and kidney abnormalities.
KW - Biochemie
Y1 - 1993
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59157
ER -
TY - JOUR
A1 - Martín, Ovidio Jiménez
A1 - Schlosser, Andreas
A1 - Furtwängler, Rhoikos
A1 - Wegert, Jenny
A1 - Gessler, Manfred
T1 - MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates
JF - Cancer Cell International
N2 - Background
Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized.
Methods
We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes.
Results
Mutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential.
Conclusions
The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.
KW - Wilms tumor
KW - MYCN
KW - MAX
KW - interactome
KW - mutation screening
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265542
VL - 21
ER -
TY - JOUR
A1 - Williams, Richard D.
A1 - Chagtai, Tasnim
A1 - Alcaide-German, Marisa
A1 - Apps, John
A1 - Wegert, Jenny
A1 - Popov, Sergey
A1 - Vujanic, Gordan
A1 - Van Tinteren, Harm
A1 - Van den Heuvel-Eibrink, Marry M
A1 - Kool, Marcel
A1 - De Kraker, Jan
A1 - Gisselsson, David
A1 - Graf, Norbert
A1 - Gessler, Manfred
A1 - Pritchard-Jones, Kathy
T1 - Multiple mechanisms of MYCN dysregulation in Wilms tumour
JF - Oncotarget
N2 - Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.
KW - integrative genomics viewer
KW - oncogene amplification
KW - sequencing data
KW - gene
KW - gain
KW - copy number
KW - somatic mutations
KW - beta-catenin
KW - histology
KW - reveals
KW - Wilms tumour
KW - MYCN
KW - DNA methylation
KW - prognostic marker
Y1 - 2015
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143471
VL - 6
IS - 9
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Bruns, Gail A. P.
T1 - Molecular mapping and cloning of the breakpoints of a chromosome 11p14.1-p13 deletion associated with the AGR syndrome
N2 - Chromosome 11p13 is frequently rearranged in individuals with the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) or parts of this syndrome. To map the cytogenetic aberrations molecularly, we screened DNA from cell Unes with known WAGR-related chromosome abnormalities for rearrangements with pulsed fleld gel (PFG) analysis using probes deleted from one chromosome 11 homolog of a WAGR patient. The first alteration was detected in a cell line from an individual with aniridia, genitourinary anomalies, mental retardation, and a deletion described as 11p14.1-p13. We have located one breakpoint close to probe HU11-164B and we have cloned both breakpoint sites as well as the junctional fragment. The breakpoints subdivide current intervals on the genetic map, and the probes for both sides will serve as important additional markers for a long-range restriction map of this region. Further characterization and sequencing of the breakpoints may yield insight into the mechanisms by which these deletions occur.
KW - Biochemie
Y1 - 1988
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59264
ER -
TY - JOUR
A1 - Vortkamp, Andrea
A1 - Gessler, Manfred
A1 - Paslier, D. Le
A1 - Elaswarapu, R.
A1 - Smith, S.
A1 - Grzeschik, Karl-Heinz
T1 - Isolation of a yeast artificial chromosome contig spanning the Greig cephalopolysyndactyly syndrome (GCPS) gene region
N2 - Disruption of the zinc finger gene GLI3 has been shown to be the cause of Greig cephalopolysyndactyly syndrome (GCPS), at least in some GCPS translocation patients. To characterize this genomic region on human chromosome 7p13, we have isolated a VAC contig of more than 1000 kb including the GLI3 gene. In this contig the gene itself spans at least 200-250 kb. A CpG island is located in the vicinity of the 5' region of the known GLI3 cDNA, implying a potential promoter region.
Y1 - 1994
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30182
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - König, A.
A1 - Arden, K.
A1 - Grundy, P.
A1 - Orkin, S. H.
A1 - Sallan, S.
A1 - Peters, C.
A1 - Ruyle, S.
A1 - Mandell, J.
A1 - Li, F.
A1 - Cavenee, W.
A1 - Bruns, G. A.
T1 - Infrequent mutation of the WT1 gene in 77 Wilms' Tumors
N2 - Homozygous deletions in Wilms' tumor DNA have been a key step in the identification and isolation of the WTI gene. Several additional loci are also postulated to contribute to Wilms' tumor formation. To assess the frequency of WTI alterations we have analyzed the WTI locus in a panel of 77 Wilms' tumors. Eight tumors showed evidence for large deletions of several hundred or thousand kilobasepairs of DNA, some of which were also cytogenetically detected. Additional intragenic mutations were detected using more sensitive SSCP analyses to scan all 10 WTI exons. Most of these result in premature stop codons or missense mutations that inactivate the remaining WTI allele. The overall frequency of WTI alterations detected with these methods is less than 15%. While some mutations may not be detectable with the methods employed, our results suggest that direct alterations of the WTI gene are present in only a small fraction of Wilms' tumors. Thus, mutations at other Wilms' tumor loci or disturbance of interactions between these genes likely play an important role in Wilms' tumor development.
KW - Wilms' tumor
KW - WTI
KW - Zinc finger gene
KW - Tumor suppressor gene
KW - Nephroblastoma
KW - Deletion analysis
KW - SSCP analysis
KW - Mutation screening
Y1 - 1994
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-34308
ER -
TY - JOUR
A1 - Wolf, Markus
A1 - Klug, Jörg
A1 - Hackenberg, Reinhard
A1 - Gessler, Manfred
A1 - Grzeschik, Karl-Heinz
A1 - Beato, Miguel
A1 - Suske, Guntram
T1 - Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines
N2 - No abstract available
KW - Biochemie
Y1 - 1992
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59206
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Konig, Anja
A1 - Moore, Jay
A1 - Qualman, Steven
A1 - Arden, Karen
A1 - Cavenee, Webster
A1 - Bruns, Gail
T1 - Homozygous inactivation of WTI in a Wilms' tumor associated with the WAGR syndrome
N2 - Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate II p 13 Wilms' tumor gene, WTI, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome II allele encompassing the WTI gene. Analysis of the remaining WTI allele in a Wilms' tumor from a WAGR patient revealed the deletion of a single nucleotide in exon 7. This mutation likely played a key role in tumor formation, as it prevents translation of the DNA-binding zinc finger domain that is essential for the function of the WTI polypeptide as a transcriptional regulator.
KW - Biochemie
Y1 - 1993
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59146
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Poustka, Annemarie
A1 - Cavenee, Webster
A1 - Neve, Rachael L.
A1 - Orkin, Stuart H.
A1 - Bruns, Gail A.
T1 - Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping
N2 - No abstract available
Y1 - 1990
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30122
ER -
TY - JOUR
A1 - Salat, Daniela
A1 - Winkler, Anja
A1 - Urlaub, Henning
A1 - Gessler, Manfred
T1 - Hey bHLH Proteins Interact with a FBXO45 Containing SCF Ubiquitin Ligase Complex and Induce Its Translocation into the Nucleus
JF - PLoS One
N2 - The Hey protein family, comprising Hey1, Hey2 and HeyL in mammals, conveys Notch signals in many cell types. The helix-loop-helix (HLH) domain as well as the Orange domain, mediate homo- and heterodimerization of these transcription factors. Although distinct interaction partners have been identified so far, their physiological relevance for Hey functions is still largely unclear. Using a tandem affinity purification approach and mass spectrometry analysis we identified members of an ubiquitin E3-ligase complex consisting of FBXO45, PAM and SKP1 as novel Hey1 associated proteins. There is a direct interaction between Hey1 and FBXO45, whereas FBXO45 is needed to mediate indirect Hey1 binding to SKP1. Expression of Hey1 induces translocation of FBXO45 and PAM into the nucleus. Hey1 is a short-lived protein that is degraded by the proteasome, but there is no evidence for FBXO45-dependent ubiquitination of Hey1. On the contrary, Hey1 mediated nuclear translocation of FBXO45 and its associated ubiquitin ligase complex may extend its spectrum to additional nuclear targets triggering their ubiquitination. This suggests a novel mechanism of action for Hey bHLH factors.
KW - ubiquitination
KW - glycerol
KW - transcription factors
KW - DNA-binding proteins
KW - immunoprecipitation
KW - protein interactions
KW - protein domains
Y1 - 2015
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125769
VL - 10
IS - 6
ER -
TY - JOUR
A1 - Vortkamp, Andrea
A1 - Gessler, Manfred
A1 - Grzeschik, Karl-Heinz
T1 - GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families
N2 - No abstract available
Y1 - 1991
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30100
ER -
TY - JOUR
A1 - Stefanovic, Sonia
A1 - Barnett, Phil
A1 - van Duijvenboden, Karel
A1 - Weber, David
A1 - Gessler, Manfred
A1 - Christoffels, Vincent M.
T1 - GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development
JF - Nature Communications
N2 - The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here we assess the transcriptional mechanism underlying this localized differentiation process. We show that atrioventricular canal-specific enhancers are GATA-binding site-dependent and act as switches that repress gene activity in the chambers. We find that atrioventricular canal-specific gene loci are enriched in H3K27ac, a marker of active enhancers, in atrioventricular canal tissue and depleted in H3K27ac in chamber tissue. In the atrioventricular canal, Gata4 activates the enhancers in synergy with Bmp2/Smad signalling, leading to H3K27 acetylation. In contrast, in chambers, Gata4 cooperates with pan-cardiac Hdac1 and Hdac2 and chamber-specific Hey1 and Hey2, leading to H3K27 deacetylation and repression. We conclude that atrioventricular canal-specific enhancers are platforms integrating cardiac transcription factors, broadly active histone modification enzymes and localized co-factors to drive atrioventricular canal-specific gene activity.
KW - biological sciences
KW - developmental biology
KW - molecular biology
Y1 - 2014
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121437
SN - 2041-1723
VL - 5
IS - 3680
ER -
TY - JOUR
A1 - Chagtai, Tasnim
A1 - Zill, Christina
A1 - Dainese, Linda
A1 - Wegert, Jenny
A1 - Savola, Suvi
A1 - Popov, Sergey
A1 - Mifsud, William
A1 - Vujanic, Gordan
A1 - Sebire, Neil
A1 - Le Bouc, Yves
A1 - Ambros, Peter F.
A1 - Kager, Leo
A1 - O`Sullivan, Maureen J.
A1 - Blaise, Annick
A1 - Bergeron, Christophe
A1 - Holmquist Mengelbier, Linda
A1 - Gisselsson, David
A1 - Kool, Marcel
A1 - Tytgat, Godelieve A.M.
A1 - van den Heuvel-Eibrink, Marry M.
A1 - Graf, Norbert
A1 - van Tinteren, Harm
A1 - Coulomb, Aurore
A1 - Gessler, Manfred
A1 - Williams, Richard Dafydd
A1 - Pritchard-Jones, Kathy
T1 - Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: a SIOP Renal Tumours Biology Consortium Study
JF - Journal of Clinical Oncology
N2 - Purpose
Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series.
Materials and Methods
WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest.
Results
One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P<.001; hazard ratio, 2.33) and OS (P=.01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss.
Conclusion
Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
KW - Poor-prognosis
KW - Mutations
KW - Gene
KW - Drosha
KW - MYCN
KW - Mechanisms
KW - Reveals
KW - Event
KW - Relapse
KW - Locus
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187478
VL - 34
IS - 26
ER -
TY - JOUR
A1 - Konig, Anja
A1 - Jakubiczka, Sybille
A1 - Wieacker, Peter
A1 - Schlösser, Hans W.
A1 - Gessler, Manfred
T1 - Further evidence that imbalance of WT1 isoforms may be involved in Denys-Drash syndrome
N2 - No abstract available
KW - Biochemie
Y1 - 1993
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59167
ER -
TY - JOUR
A1 - Poulat, F.
A1 - Morin, D.
A1 - Konig, A.
A1 - Brun, P.
A1 - Giltay, J.
A1 - Sultan, C.
A1 - Dumas, R.
A1 - Gessler, Manfred
A1 - Berta, P.
T1 - Distinct molecular origins for Denys-Drash and Frasier syndromes
N2 - The direct involvment of the Wilm's tumor suppressor gene (WTl) in Denys-Drash syndrome through mutations within exons 8 or 9 has recently been established. The absence of such alterations in three patients with Frasier syndrome provides a molecular basis for distinguishing these two syndromes that are associated with streak gonads, pseudohermaphroditism and renal failure.
KW - Biochemie
Y1 - 1993
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59172
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Barnekow, Angelika
T1 - Differential expression of the cellular oncogenes c-src and c-yes in embryonal and adult chicken tissues
N2 - The cellular onc-genes c-src and c-yes are expressed very differently during chicken embryonic development. The c-src mRNA and its translational product are detectable at high levels in brain extracts of chicken embryos and adult chickens, whereas muscle extracts show an age-dependent decrease in the amounts of c-src-specific mRNA and pp60c-src kinase activity. In contrast, the Ievels of c-yes mRNA in brain, heart, and muscle are relatively low in early embryonic stages and increase later on to values comparable to those found for liver, while in adult animals the pattern of c-yes expression is similar to that of the c-src gene. From the close correlation between the Ievels of pp60c-src, its enzymatic activity, and its corresponding mRNA at a given stage of development and in given tissues, it appears that the expression of pp60c-src is primarily controlled at the level of transcription. It is suggested that because of the different patterns of expression, the two cellular oncogenes, c-src and c-yes, play different roles in cell proliferation during early embryonic stages as weil as in ensuing differentiation processes.
KW - Biochemie
Y1 - 1984
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59289
ER -
TY - JOUR
A1 - Vortkamp, Andrea
A1 - Franz, Thomas
A1 - Gessler, Manfred
A1 - Grzeschik, Karl-Heinz
T1 - Deletion of GLI3 supports the homology of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutant extra toes (Xt)
N2 - No abstract available
Y1 - 1992
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30166
ER -
TY - JOUR
A1 - Welter, Nils
A1 - Wagner, Angelo
A1 - Furtwängler, Rhoikos
A1 - Melchior, Patrick
A1 - Kager, Leo
A1 - Vokuhl, Christian
A1 - Schenk, Jens-Peter
A1 - Meier, Clemens Magnus
A1 - Siemer, Stefan
A1 - Gessler, Manfred
A1 - Graf, Norbert
T1 - Correction: Welter et al. Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome. Cancers 2021, 13, 5016
JF - Cancers
N2 - In the original article [1] there was a mistake in Table 2 as published. Table 2 contains wrong percentages in lines Bilateral disease and Patients with CPS or GU. For this reason the table should be replaced with the correct one as shown below.
KW - nephroblastomatosis
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250135
SN - 2072-6694
VL - 13
IS - 22
ER -
TY - JOUR
A1 - Schwarz, Klaus
A1 - Hameister, Horst
A1 - Gessler, Manfred
A1 - Grzeschik, Karl-Heinz
A1 - Hansen-Hagge, Thomas E.
A1 - Bartram, Claus R.
T1 - Confirmation of the localization of the human recombination activating gene 1 (RAG1) to chromosome 11p13
N2 - The human recombination activating gene 1 (RAGl) has previously been mapped to chromosomes 14q and 11 p. Here we confirm the chromosome 11 assignment by two independent approaches: autoradiographic and fluorescence in situ hybridization to metaphase spreads and analysis of human-hamster somatic cell hybrid DNA by the polymerase chain reaction (PCR) and Southern blotting. Our results unequivocally localize RAG1 to llp13.
KW - Biochemie
Y1 - 1994
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59136
ER -
TY - RPRT
A1 - Gessler, Manfred
A1 - Simola, Kalle O.
A1 - Bruns, Gail A. P.
T1 - Cloning of breakpoints of a chromosome translocation identifies the AN2 locus
N2 - Chromosome translocations involving llpl3 have been associated with familial aniridia in two kindreds highlighting the chromosomal localization of the AN2 locus. This locus is also part of the WAGR complex (Wilros tumor, aniridia, genitourinary abnormalities, and mental retardation). In one kindred, the translocation is associated with a deletion, and probes for this region were used to identify and clone the breakpoints of the translocation in the second kindred. Comparison of phage restriction maps exclude the presence of any sizable deletion in this case. Sequences at the chromosome 11 breakpoint are conserved in multiple species, suggesting that the translocation falls within the AN2 gene.
Y1 - 1989
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30177
ER -
TY - JOUR
A1 - Welter, Nils
A1 - Wagner, Angelo
A1 - Furtwängler, Rhoikos
A1 - Melchior, Patrick
A1 - Kager, Leo
A1 - Vokuhl, Christian
A1 - Schenk, Jens-Peter
A1 - Meier, Clemens Magnus
A1 - Siemer, Stefan
A1 - Gessler, Manfred
A1 - Graf, Norbert
T1 - Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome
JF - Cancers
N2 - (1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.
KW - nephroblastoma
KW - clinical malformations
KW - cancer predisposition syndromes
KW - tumor surveillance
KW - outcome
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248434
SN - 2072-6694
VL - 13
IS - 19
ER -
TY - JOUR
A1 - Schmitt, Jana
A1 - Keller, Andreas
A1 - Nourkami-Tutdibi, Nasenien
A1 - Heisel, Sabrina
A1 - Habel, Nunja
A1 - Leidinger, Petra
A1 - Ludwig, Nicole
A1 - Gessler, Manfred
A1 - Graf, Norbert
A1 - Berthold, Frank
A1 - Lenhof, Hans-Peter
A1 - Meese, Eckart
T1 - Autoantibody Signature Differentiates Wilms Tumor Patients from Neuroblastoma Patients
JF - PLoS ONE
N2 - Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor.
KW - Heparan-sulfate
KW - N-Myc
KW - Serum autoantibodies
KW - Suppressors EXT1
KW - Neuro-blastoma
KW - Allelic loss
KW - Lung-cancer
KW - Children
KW - Amplification
KW - Therapy
Y1 - 2011
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133794
VL - 6
IS - 12
ER -
TY - JOUR
A1 - Higgins, M. J.
A1 - Smilinich, N. J.
A1 - Sait, S.
A1 - Koenig, A.
A1 - Pongratz, J.
A1 - Gessler, Manfred
A1 - Richard III., C. W.
A1 - James, M. R.
A1 - Sanford, J. P.
A1 - Kim, B.-W.
A1 - Cattelane, J.
A1 - Nowak, N. J.
A1 - Winterpacht, A.
A1 - Zabel, B. U.
A1 - Munroe, D. J.
A1 - Bric, E.
A1 - Housman, D. E.
A1 - Jones, C.
A1 - Nakamura, Y.
A1 - Gerhard, D. S.
A1 - Shows, T. B.
T1 - An Ordered NotI Fragment Map of Human Chromosome Band 11p15
N2 - An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band llpl5. Forty-two probes, including 11 NotI-linking cosmids, were subregionaUy mapped to llpl5 using a subset of the Jl-deletion hybrids. These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed-field gel electrophoresis. Thirty-nine distinct NotI fragments were detected encompassing approximately 85% of the estimated length of llp15. The predicted order of the gene loci used is cenMYODI- PTH-CALCA-ST5-RBTNI-HPX-HBB-RRMlTH/ INS!1GF2-H19-CTSD-MUC2-DRD4-HRAS-RNHtel. This map wiu allow higher resolution mapping of new Ilp15 markers, facilitate positional cloning of disease genes, and provide a framework for the physical mapping of llp15 in clone contigs.
KW - Genom / Genkartierung / Genanalyse
Y1 - 1994
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45766
ER -
TY - JOUR
A1 - Barnekow, Angelika
A1 - Gessler, Manfred
T1 - Activation of the pp60\(^{c-src}\) kinase during differentiation of monomyelocytic cells in vitro
N2 - Tbe proto-oncogene c-src, the cellular homolog of the Rous sarcoma virus (RSV) transforming gene v-src, is expressed in a tissue-specific and age-dependent manner. Its physiological function, although still unknown, appears to be more closely related to differentiation processes than to proliferation processes. To obtain more information about the physiological role of the c-src gene in cells, we have studied differentiation-dependent alterations using the human HL-60 leukaemia cell line as a model system. Induction of monocytic and granulocytic differentiation of HL-60 cells by 12-0-tetradecanoylphorbol-13-acetate (TPA) and dimethylsulfoxide (DMSO) is associated with an activation of the pp60c-src tyrosine kinase, but not with increased c-src gene expression. Control experiments exclude an interaction of TPA and DMSO themselves with the pp60c-src kinase.
KW - Biochemie
KW - c-src
KW - differentiation
KW - protein tyrosine kinase
KW - protooncogene
Y1 - 1986
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59278
ER -
TY - JOUR
A1 - Schwartz, Faina
A1 - Neve, Rachel
A1 - Eisenman, Robert
A1 - Gessler, Manfred
A1 - Bruns, Gail
T1 - A WAGR region gene between PAX-6 and FSHB expressed in fetal brain
N2 - Developmental delay or mental retardation is a frequent component of multi-system anomaly syndromes associated with chromosomal deletions. Isolation of genes involved in the mental dysfunction in these disorders should define loci important in brain formation or function. We have identified a highly conserved locus in the distal part of 11 p 13 that is prominently expressed in fetal brain. Minimal expression is observed in a number of other fetal tissues. The gene maps distal to PAX-6 but proximal to the loci for brain-derived neurotrophic factor (BDNF) and the beta subunit of follicle stimulating hormone (FSHB), within a region previously implicated in the mental retardation component of some WAGR syndrome patients. Within fetal brain, the corresponding transcript is prominent in frontal, motor and primary visual cortex as weil as in the caudate-putamen. The characteristics of this gene, including the striking evolutionary conservation at the locus, suggest that the encoded protein may function in brain development.
KW - Biochemie
Y1 - 1994
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59125
ER -
TY - JOUR
A1 - Vortkamp, A.
A1 - Thias, U.
A1 - Gessler, Manfred
A1 - Rosenkranz, W.
A1 - Kroisel, P. M.
A1 - Tommerup, N.
A1 - Kruger, G.
A1 - Gotz, J.
A1 - Pelz, L.
A1 - Grzeschik, Karl-Heinz
T1 - A somatic cell hybrid panel and DNA probes for physical mapping of human chromosome 7p
N2 - No abstract available
KW - Biochemie
Y1 - 1991
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59217
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Bruns, G. A. P.
T1 - A physical map around the WAGR complex on the short arm of chromosome 11
N2 - A long-range restriction map of part of the short arm of ehromosome 11 including the WAGR region has been constructed using pulsed-field gel electrophoresis and a number of infrequently cutting restriction enzymes. A total of 15.4 Mbp has been mapped in detall, extending from proximal 11p14 to the distal part of 11p12. The map localizes 35 different DNA probes and reveals at least nine areas with features eharaeteristle of BTF islands, some of which may be candidates for the different loci underlying the phenotype of the WAGR syndrome. This map will furthermore allow screening of DNA from individuals with WAGR-related phenotypes and from Wilms tumors for associated chromosomal rearrangements.
KW - Biochemie
Y1 - 1989
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59246
ER -
TY - JOUR
A1 - Gessler, Manfred
A1 - Thomas, G. H.
A1 - Couillin, P.
A1 - Junien, C.
A1 - McGillivray, B. C.
A1 - Hayden, M.
A1 - Jaschek, G.
A1 - Bruns, G. A.
T1 - A deletion map of the WAGR region on chromosome II
N2 - The WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) region has been assigned to chromosome 11p13 on the basis of overlapping constitutional deletions found in affected individuals. We have utilized 31 DNA probes which map to the WAGR deletion region, together with six reference loci and 13 WAGR-related deletions, to subdivide this area into 16 intervals. Specific intervals have been correlated with phenotypic features, leading to the identification of individual subregions for the aniridia and Wilms tumor loci. Delineation, by specific probes, of multiple intervals above and below the critical region and of five intervals within the overlap area provides a framework map for molecular characterization of WAGR gene loci and of deletion boundary regions.
KW - Biochemie
Y1 - 1989
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-59255
ER -