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Cancers
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Advances in Genetics and Epigenetics of Bladder Cancer
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Advances in Genetics and Epigenetics of Bladder Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 4366

Special Issue Editor

Dr. Michael Rose

E-Mail Website
Guest Editor
Oncological Pathology Group, Institute of Pathology, Hospital of the RWTH Aachen University, Pauwelsstr.30, 52074 Aachen, Germany
Interests: bladder cancer; epigenetics; (epi)genetic biomarkers; DNA damage response; class II tumor suppressor genes; cancer metastasis; tumor evolution; tumor microenvironment; drug development

Special Issue Information

Dear Colleagues,

The urinary bladder and the upper urothelial tract are locations of multifocal and recurrent urothelial tumors with or without tumor progression. Since 2004, genetic data have been integrated into the WHO classification, while the Cancer Genome Atlas (TCGA) and a plethora of new techniques to assess genetic changes have provided thought-provoking data. Although changes at the genomic level are the baseline of a tumor’s molecular profile, reflecting ancestral inherited information of clonal expansions of tumor cells, this single dimension does not provide sufficient insight into the molecular complexity of tumor development. Additionally, epigenetic mechanisms, such as DNA methylation, histone modifications, and its crosstalk, also shape the active and inactive states of the blueprint, which then results in the information which is actually translated into the effector protein level. DNA methylation has been recently presented as an initial field effect in the bladder mucosa associated with a background of heterogeneous mutational patterns that function as a potential early cancer driver. Thus, both genetics and epigenetics hold clues to identify novel biomarkers for diagnosis, risk stratification or therapeutic approaches and to explain the development of heterogeneous cancer (cell) phenotypes.

To summarize and provide an overview of recent knowledge, this Special Issue will span various topics ranging from genetic and epigenetic changes in early- (carcinoma in situ) and late-stage muscle-invasive bladder cancers (MIBC) over actionable mutation and genetic alterations, such as biomarkers, to mechanisms of controlling histone modifiers in urothelial tumorigenesis, with special emphasis on prognostic and therapeutic options for individual patients.

Dr. Michael Rose
Guest Editor

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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
  • molecular pathology
  • next-generation sequencing
  • liquid biopsy
  • genetic instability
  • mutations
  • SNV
  • CNV
  • gene fusion
  • DNA methylation
  • histone modifications
  • non-coding RNAs

Published Papers (4 papers)

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19 pages, 4868 KiB  
Article
Lysine Methyltransferase 9 (KMT9) Is an Actionable Target in Muscle-Invasive Bladder Cancer
by Sainab Totonji, Anna Ramos-Triguero, Dominica Willmann, Manuela Sum, Sylvia Urban, Helena Bauer, Astrid Rieder, Sheng Wang, Holger Greschik, Eric Metzger and Roland Schüle
Cancers 2024, 16(8), 1532; https://doi.org/10.3390/cancers16081532 - 17 Apr 2024
Viewed by 387
Abstract
Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified KMT9, an obligate heterodimer composed of KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung, [...] Read more.
Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified KMT9, an obligate heterodimer composed of KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung, and colon cancer. While the overexpression of KMT9α was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients’ tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date. In this study, we show that KMT9 regulates proliferation, migration, and invasion of various MIBC cell lines with different genetic mutations. KMT9α depletion results in the differential expression of genes regulating the cell cycle, cell adhesion, and migration. Differentially expressed genes include oncogenes such as EGFR and AKT1 as well as mediators of cell adhesion or migration such as DAG1 and ITGA6. Reduced cell proliferation upon KMT9α depletion is also observed in Pten/Trp53 knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9α mutant. In accordance with the idea that the catalytic activity of KMT9 is required for the control of cellular processes in MIBC, a recently developed small-molecule inhibitor of KMT9 (KMI169) also impairs cancer cell proliferation. Since KMT9α depletion also restricts the growth of xenografts in mice, our data suggest that KMT9 is an actionable novel therapeutic target for the treatment of MIBC. Full article
(This article belongs to the Special Issue Advances in Genetics and Epigenetics of Bladder Cancer)
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18 pages, 4942 KiB  
Article
Downregulated RBM5 Enhances CARM1 Expression and Activates the PRKACA/GSK3β Signaling Pathway through Alternative Splicing-Coupled Nonsense-Mediated Decay
by Yanping Zhang, Fang Li, Zhenwei Han, Zhihai Teng, Chenggen Jin, Hao Yuan, Sihao Zhang, Kexin Sun and Yaxuan Wang
Cancers 2024, 16(1), 139; https://doi.org/10.3390/cancers16010139 - 27 Dec 2023
Cited by 1 | Viewed by 825
Abstract
Downregulated RNA-binding motif protein 5 (RBM5) promotes the development and progression of various tumors, including bladder cancer (BC). Alternative splicing (AS) plays a crucial role in the progression of cancer by producing protein isomers with different functions or by promoting nonsense-mediated mRNA decay [...] Read more.
Downregulated RNA-binding motif protein 5 (RBM5) promotes the development and progression of various tumors, including bladder cancer (BC). Alternative splicing (AS) plays a crucial role in the progression of cancer by producing protein isomers with different functions or by promoting nonsense-mediated mRNA decay (NMD). However, whether RBM5 modulates the progression of BC through AS-NMD remains unexplored. In this study, we revealed that the downregulation of RBM5 expression promoted the expression of coactivator-associated arginine methyltransferase 1 (CARM1) in BC cells and tissues. Increased expression of CARM1 facilitated the activation of the Wnt/β-catenin axis and cell proliferation, which then contributed to the poor prognosis of patients with BC. Interestingly, RBM5 bound directly to CARM1 mRNA and participated in AS-NMD, downregulating the expression of CARM1. In addition, we revealed that protein kinase catalytic subunit alpha (PRKACA) functioned as a phosphorylated kinase of GSK3β, was regulated by CARM1 at the transcription level, and promoted the growth and progression of BC cells. Furthermore, in this study, we demonstrated a regulatory mechanism of Wnt/β-catenin activation through the RBM5/CARM1/PRKACA axis and identified a novel potential target for treating BC. Full article
(This article belongs to the Special Issue Advances in Genetics and Epigenetics of Bladder Cancer)
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18 pages, 4065 KiB  
Article
Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A
by Omid Fotouhi, Sheikh Nizamuddin, Stephanie Falk, Oliver Schilling, Ruth Knüchel-Clarke, Martin L. Biniossek and H. T. Marc Timmers
Cancers 2023, 15(12), 3117; https://doi.org/10.3390/cancers15123117 - 08 Jun 2023
Cited by 1 | Viewed by 1466
Abstract
The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of [...] Read more.
The UTX/KDM6A histone H3K27 demethylase plays an important role in development and is frequently mutated in cancers such as urothelial cancer. Despite many studies on UTX proteins, variations in mRNA splicing have been overlooked. Using Nanopore sequencing, we present a comprehensive analysis of UTX/KDM6A splicing events in human cell lines and in tissue samples from bladder cancer cases and normal epithelia. We found that the central region of UTX mRNAs encoded by exons 12 to 17 undergoes extensive alternative splicing. Up to half of all stable mRNAs (8–48% in bladder tissues and 18–58% in cell lines) are represented by the UTX canonical isoform lacking exon 14 encoding a nuclear localization sequence, and hence exon 14-containing UTX isoforms exclusively localize to the nucleus, unlike the cytonuclear localization of the canonical isoform. Chromatin association was also higher for exon-14-containing isoforms compared to the canonical UTX. Using quantitative mass spectrometry, we found that all UTX isoforms integrated into the MLL3 and MLL4, PR-DUB and MiDAC complexes. Interestingly, one of the novel UTX isoforms, which lacks exons 14 and 16, fails to interact with PR-DUB and MiDAC complex members. In conclusion, UTX mRNAs undergo extensive alternative splicing, which controls the subcellular localization of UTX and its interactions with other chromatin regulatory complexes. Full article
(This article belongs to the Special Issue Advances in Genetics and Epigenetics of Bladder Cancer)
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14 pages, 1368 KiB  
Systematic Review
Methylenetetrahydrofolate Reductase C677T (rs1801133) Polymorphism Is Associated with Bladder Cancer in Asian Population: Epigenetic Meta-Analysis as Precision Medicine Approach
by Athaya Febriantyo Purnomo, Besut Daryanto, Kurnia Penta Seputra, Taufiq Nur Budaya, Nurul Cholifah Lutfiana, Fahrul Nurkolis, Sanghyun Chung, Jin Young Suh, Moon Nyeo Park, Byung-Kwan Seo and Bonglee Kim
Cancers 2023, 15(17), 4402; https://doi.org/10.3390/cancers15174402 - 02 Sep 2023
Cited by 3 | Viewed by 1122
Abstract
The etiology of bladder cancer remains unclear. This study investigates the impact of gene polymorphisms, particularly methylenetetrahydrofolate reductase gene (MTHFR), on bladder cancer susceptibility, focusing on the rs1801133 single-nucleotide polymorphism (SNP). A meta-analysis was conducted after systematically reviewing the MTHFR gene literature, adhering [...] Read more.
The etiology of bladder cancer remains unclear. This study investigates the impact of gene polymorphisms, particularly methylenetetrahydrofolate reductase gene (MTHFR), on bladder cancer susceptibility, focusing on the rs1801133 single-nucleotide polymorphism (SNP). A meta-analysis was conducted after systematically reviewing the MTHFR gene literature, adhering to PRISMA guidelines and registering in PROSPERO (CRD42023423064). Seven studies were included, showing a significant association between the MTHFR C677T (rs1801133) polymorphism and bladder cancer susceptibility. Individuals with the T-allele or TT genotype had a higher likelihood of bladder cancer. In the Asian population, the overall analysis revealed an odds ratio (OR) of 1.15 (95% CI 1.03–1.30; p-value = 0.03) for T-allele versus C-allele and an OR of 1.34 (95% CI 1.04–1.72; p-value = 0.02) for TT genotype versus TC+CC genotype. The CC genotype, however, showed no significant association with bladder cancer. Notably, epigenetic findings displayed low sensitivity but high specificity, indicating reliable identified associations while potentially overlooking some epigenetic factors related to bladder cancer. In conclusion, the MTHFR T-allele and TT genotype were associated with increased bladder cancer risk in the Asian population. These insights into genetic factors influencing bladder cancer susceptibility could inform targeted prevention and treatment strategies. Further research is warranted to validate and expand these findings. Full article
(This article belongs to the Special Issue Advances in Genetics and Epigenetics of Bladder Cancer)
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