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Genetics and Genomics of Bladder Cancer
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Genetics and Genomics of Bladder Cancer

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 14713

Special Issue Editors

Prof. Dr. Nadine Gaisa

E-Mail Website
Guest Editor
Institute of Pathology, University Hospital RWTH Aachen University, 52062 Aachen, Germany
Interests: cancer; bladder cancer; tumorigenesis; tumor heterogeneity
Prof. Dr. Ruth Knüchel-Clarke

E-Mail Website
Guest Editor
Institute of Pathology, University Hospital RWTH Aachen University, 52074 Aachen, Germany
Interests: bladder cancer; precursor lesions; early detection

Special Issue Information

Dear Colleagues,

The urinary bladder and the upper urothelial tract are locations for endoscopically accessible multifocal and recurrent urothelial tumors with or without tumor progression. In analogy to, e.g., oral squamous lesions, this setting has stimulated research about the clonal origin of tumors versus field cancerization. Since 2004, genetic data have been integrated into the WHO-classification and in this century the results of The Cancer Genome Atlas (TCGA) and a plethora of new techniques to assess genetic changes have provided thought-provoking data.

To summarize and provide an overview of recent knowledge, this Special Issue will span various topics ranging from bladder tumor preposition over tumorigenesis to molecular data on metastasizing urothelial tumors and its variants with special emphasis on prognostic and therapeutic options for the individual patients.

Prof. Dr. Dr. Nadine Gaisa
Prof. Dr. Ruth Knüchel-Clarke
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bladder cancer
  • Urothelium
  • Molecular pathology
  • Next generation sequencing
  • Liquid biopsy
  • Intravesical therapy
  • Neoadjuvant therapy
  • Genetic instability
  • SNV
  • CNV
  • Gene fusion

Published Papers (6 papers)

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Research

12 pages, 2232 KiB  
Article
Proteasomal Processing Immune Escape Mechanisms in Platinum-Treated Advanced Bladder Cancer
by Michael Wessolly, Fabian D. Mairinger, Thomas Herold, Boris Hadaschik, Tibor Szarvas and Henning Reis
Genes 2022, 13(3), 422; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030422 - 25 Feb 2022
Cited by 3 | Viewed by 1774
Abstract
In recent years, the number and type of treatment options in advanced bladder cancer (BC) have been rapidly evolving. To select an effective therapy and spare unnecessary side effects, predictive biomarkers are urgently needed. As the host’s anti-cancer immune response is by far [...] Read more.
In recent years, the number and type of treatment options in advanced bladder cancer (BC) have been rapidly evolving. To select an effective therapy and spare unnecessary side effects, predictive biomarkers are urgently needed. As the host’s anti-cancer immune response is by far the most effective system to impede malignant tumor growth, immune system-based biomarkers are promising. We have recently described altered proteasomal epitope processing as an effective immune escape mechanism to impair cytotoxic T-cell activity. By altering the neoantigens’ characteristics through different proteasomal peptide cleavage induced by non-synonymous somatic mutations, the ability for T-cell activation was decreased (“processing escapes”). In the present study, we analyzed primary chemo-naïve tissue samples of 26 adjuvant platinum-treated urothelial BC patients using a targeted next-generation sequencing panel followed by the epitope determination of affected genes, a machine-learning based prediction of epitope processing and proteasomal cleavage and of HLA-affinity as well as immune activation. Immune infiltration (immunohistochemistries for CD8, granzyme B, CD45/LCA) was digitally quantified by a pathologist and clinico-pathological and survival data were collected. We detected 145 epitopes with characteristics of a processing escape associated with a higher number of CD8-positive but lower number of granzyme B-positive cells and no association with PD-L1-expression. In addition, a high prevalence of processing escapes was associated with unfavorable overall survival. Our data indicate the presence of processing escapes in advanced BC, potentially creating a tumor-promoting pro-inflammatory environment with lowered anti-cancerous activity and independence from PD-L1-expression. The data also need to be prospectively validated in BC treated with immune therapy. Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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13 pages, 34517 KiB  
Article
Molecular Characterization of Muellerian Tumors of the Urinary Tract
by Nadina Ortiz-Brüchle, Sophie Wucherpfennig, Michael Rose, Stefan Garczyk, Simone Bertz, Arndt Hartmann, Henning Reis, Tibor Szarvas, András Kiss, Felix Bremmer, Reinhard Golz, Ruth Knüchel and Nadine T. Gaisa
Genes 2021, 12(6), 880; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060880 - 07 Jun 2021
Cited by 5 | Viewed by 2220
Abstract
In the 2016 WHO classification of genitourinary tumors Muellerian tumors of the urinary tract (MTUT) comprise clear cell adenocarcinomas and endometrioid carcinomas. Since these rare tumors remained understudied, we aimed to characterize their molecular background by performing DNA- and RNA-based targeted panel sequencing. [...] Read more.
In the 2016 WHO classification of genitourinary tumors Muellerian tumors of the urinary tract (MTUT) comprise clear cell adenocarcinomas and endometrioid carcinomas. Since these rare tumors remained understudied, we aimed to characterize their molecular background by performing DNA- and RNA-based targeted panel sequencing. All tumors (n = 11) presented single nucleotide alterations (SNVs), with ARID1A mutations being the most prevalent (5/11, 45%). Besides frequent ARID1A mutations, loss of ARID1A protein is not a suitable marker since protein expression is (partly) preserved also in mutated cases. Copy number alterations (CNVs) were found in 64% of cases (7/11), exclusively gene amplifications. Interestingly, a functionally relevant RSPO2 gene fusion/microdeletion was discovered in the endometrioid adenocarcinoma case. Comparing our findings with mutational profiles of other tumor entities, absence of TERT promoter mutations argues for a non-urothelial origin. No similarities were also found between MTUT and kidney cancers while parallels were observed for specific SNVs with endometrial carcinomas. In conclusion, immunohistochemical PAX8-positivity and lack of TERT promoter mutations could serve as key diagnostic features in difficult cases. Thus, understanding the molecular background of these tumors helps to refine treatment options and offers the possibility of targeted therapies in cases where needed. Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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17 pages, 3087 KiB  
Article
Neuropilin-2 and Its Transcript Variants Correlate with Clinical Outcome in Bladder Cancer
by Sarah Förster, Maryam Givehchi, Katja Nitschke, Thomas Mayr, Kerstin Kilian, Samikshan Dutta, Kaustubh Datta, Philipp Nuhn, Zoran Popovic, Michael H. Muders and Philipp Erben
Genes 2021, 12(4), 550; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12040550 - 09 Apr 2021
Cited by 5 | Viewed by 2175
Abstract
Urothelial bladder cancer ranks among the 10 most frequently diagnosed cancers worldwide. In our previous study, the transmembrane protein neuropilin-2 (NRP2) emerged as a predictive marker in patients with bladder cancer. NRP2 consists of several splice variants; the most abundant of these, NRP2a [...] Read more.
Urothelial bladder cancer ranks among the 10 most frequently diagnosed cancers worldwide. In our previous study, the transmembrane protein neuropilin-2 (NRP2) emerged as a predictive marker in patients with bladder cancer. NRP2 consists of several splice variants; the most abundant of these, NRP2a and NRP2b, are reported to have different biological functions in lung cancer progression. For other cancer types, there are no published data on the role of these transcript variants in cancer progression and the clinical outcome. Here, we correlate NRP2 and its two most abundant transcript variants, NRP2A and NRP2B, with the clinical outcome using available genomic data with subsequent validation in our own cohort of patients with muscle-invasive bladder cancer. In addition to NRP2, NRP1 and the NRP ligands PDGFC and PDGFD were studied. Only NRP2A emerged as an independent prognostic marker for shorter cancer-specific survival in muscle-invasive bladder cancer in our cohort of 102 patients who underwent radical cystectomy between 2008 and 2014 with a median follow-up time of 82 months. Additionally, we demonstrate that high messenger expression of NRP2, NRP1, PDGFC and PDGFD associates with a more aggressive disease (i.e., a high T stage, positive lymph node status and reduced survival). Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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20 pages, 4292 KiB  
Article
Downregulation of Cell Cycle and Checkpoint Genes by Class I HDAC Inhibitors Limits Synergism with G2/M Checkpoint Inhibitor MK-1775 in Bladder Cancer Cells
by Michèle J. Hoffmann, Sarah Meneceur, Katrin Hommel, Wolfgang A. Schulz and Günter Niegisch
Genes 2021, 12(2), 260; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020260 - 11 Feb 2021
Cited by 13 | Viewed by 2481
Abstract
Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell [...] Read more.
Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted. Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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10 pages, 2231 KiB  
Article
TERT Promoter Mutation Analysis of Whole-Organ Mapping Bladder Cancers
by Veronika Weyerer, Markus Eckstein, Pamela L. Strissel, Adrian Wullweber, Fabienne Lange, Lars Tögel, Carol I. Geppert, Danijel Sikic, Helge Taubert, Sven Wach, Bernd Wullich, Arndt Hartmann, Robert Stoehr and Johannes Giedl
Genes 2021, 12(2), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020230 - 05 Feb 2021
Cited by 11 | Viewed by 2044
Abstract
Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most [...] Read more.
Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (−57, −124 or −146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development. Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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15 pages, 2128 KiB  
Article
SWI/SNF Alterations in Squamous Bladder Cancers
by Fabian Achenbach, Michael Rose, Nadina Ortiz-Brüchle, Lancelot Seillier, Ruth Knüchel, Veronika Weyerer, Arndt Hartmann, Ronja Morsch, Angela Maurer, Thorsten H. Ecke, Stefan Garczyk and Nadine T. Gaisa
Genes 2020, 11(11), 1368; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11111368 - 19 Nov 2020
Cited by 3 | Viewed by 2752
Abstract
Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key [...] Read more.
Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key components of the SWI/SNF complex considering the co-occurrence of genetic driver mutations and PD-L1 expression as indicators for therapeutic implications. Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation. Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116). Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed. Finally, a rare number of sq-BLCA samples were characterized by both ARID1A protein loss and strong PD-L1 expression suggesting a putative benefit upon immune checkpoint inhibitor therapy. Hence, for the first time, our data revealed expression loss of SWI/SNF subunits in sq-BLCA, highlighting ARID1A as a putative target of a small subgroup of patients eligible for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Genetics and Genomics of Bladder Cancer)
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