Bladder Cancer in the Genomic Era

Context.— Bladder cancer is a heterogeneous disease that exhibits a wide spectrum of clinical and pathologic features. The classification of bladder cancer has been traditionally based on morphologic assessment with the aid of immunohistochemistry. However, recent genomic studies have revealed that distinct alterations of DNA and RNA in bladder cancer may underlie its diverse clinicopathologic features, leading to a novel molecular classification of this common human cancer. Objective.— To update recent developments in genomic characterization of bladder cancer, which may shed insights on the molecular mechanisms underlying the origin of bladder cancer, dual-track oncogenic pathways, intrinsic molecular subtyping, and development of histologic variants. Data Sources.— Peer-reviewed literature retrieved from PubMed search and authors' own research. Conclusions.— Bladder cancer is likely to arise from different uroprogenitor cells through papillary/luminal and nonpapillary/basal tracks. The intrinsic molecular subtypes of bladder cancer referred to as luminal and basal exhibit distinct expression signatures, clinicopathologic features, and sensitivities to standard chemotherapy. Genomic characterization of bladder cancer provides new insights to understanding the biological nature of this complex disease, which may lead to more effective treatment.

Download Full-text

The Analysis of PTPN6 for Bladder Cancer: An Exploratory Study Based on TCGA

Disease Markers ◽

10.1155/2020/4312629 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Chengquan Shen ◽

Jing Liu ◽

Jirong Wang ◽

Xiaokun Yang ◽

Haitao Niu ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

Survival Analysis ◽

Prognostic Value ◽

Molecular Mechanisms ◽

Tyrosine Phosphatase ◽

Gene Set Enrichment Analysis ◽

Expression Level ◽

Pathologic Features ◽

The Relationship

PTPN6 (protein tyrosine phosphatase nonreceptor type 6), a tyrosine phosphatase, is known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Previous studies have demonstrated that PTPN6 expression is relatively elevated in several malignancies. However, the role of PTPN6 in bladder cancer (BC) remains unclear. The purpose of this study was to explore the prognostic value of PTPN6 in BC. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify the expression level of PTPN6 in BC. The relationship between clinical pathologic features and PTPN6 were analyzed with the Wilcoxon signed-rank test. The prognostic and predictive value of PTPN6 was evaluated by survival analysis and nomogram. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential molecular mechanisms of PTPN6 in BC. Finally, Tumor Immune Estimation Resource (TIMER) was applied to investigate the relationship between PTPN6 and immune cell infiltration in the tumor microenvironment. Results indicated that PTPN6 was overexpressed in BC tissues compared with normal bladder tissues and was significantly correlated with grade, stage, T, and N. Survival analysis showed that low expression of PTPN6 was significantly related to the poor overall survival (OS) in BC patients. Coexpression analysis showed that PTPN6 and TNFRSF14 (Tumor necrosis factor receptor superfamily member 14) have a close correlation in BC. GSEA showed that multiple cancer-associated signaling pathways are differentially enriched in the PTPN6 high expression phenotype. Moreover, the expression level of PTPN6 was positively associated with the infiltration of B cells, CD4+T cells, dendritic cells, and neutrophils and negatively associated with CD8+ T cells and macrophages in BC. In conclusion, we identified that PTPN6 may be a novel prognostic biomarker in BC based on the TCGA database. Further clinical trials are needed to confirm our observations and mechanisms underlying the prognostic value of PTPN6 in BC also deserve further experimental exploration.

Download Full-text

Genomic Characterization of Antimicrobial Resistance, Virulence, and Phylogeny of the Genus Ochrobactrum

Antibiotics ◽

10.3390/antibiotics9040177 ◽

2020 ◽

Vol 9 (4) ◽

pp. 177 ◽

Cited By ~ 2

Author(s):

Yael Yagel ◽

Stephanie Sestito ◽

Yair Motro ◽

Anat Shnaiderman-Torban ◽

Boris Khalfin ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Virulence Genes ◽

Opportunistic Infections ◽

Species Classification ◽

Genome Phylogeny ◽

Genomic Characterization ◽

Specific Species ◽

Lactamase Gene

Ochrobactrum is a ubiquitous Gram-negative microorganism, mostly found in the environment, which can cause opportunistic infections in humans. It is almost uniformly resistant to penicillins and cephalosporins through an AmpC-like β-lactamase enzyme class (OCH). We studied 130 assembled genomes, of which 5 were animal-derived isolates recovered in Israel, and 125 publicly available genomes. Our analysis focused on antimicrobial resistance (AMR) genes, virulence genes, and whole-genome phylogeny. We found that 76% of Ochrobactrum genomes harbored a blaOCH β-lactamase gene variant, while 7% harbored another AmpC-like gene. No virulence genes other than lipopolysaccharide-associated genes were found. Core genome multilocus sequence typing clustered most samples to known species, but neither geographical clustering nor isolation source clustering were evident. When analyzing the distribution of different blaOCH variants as well as of the blaOCH-deficient samples, a clear phylogenomic clustering was apparent for specific species. The current analysis of the largest collection to date of Ochrobactrum genomes sheds light on the resistome, virulome, phylogeny, and species classification of this increasingly reported human pathogen. Our findings also suggest that Ochrobactrum deserves further characterization to underpin its evolution, taxonomy, and antimicrobial resistance.

Download Full-text

Metagenomic characterization of lysine acetyltransferases in human cancer and their association with clinicopathologic features

Cancer Science ◽

10.1111/cas.14385 ◽

2020 ◽

Vol 111 (5) ◽

pp. 1829-1839 ◽

Cited By ~ 3

Author(s):

Yuanyuan Jiang ◽

Xuhui Guo ◽

Lanxin Liu ◽

Shomita Rode ◽

Rui Wang ◽

...

Keyword(s):

Human Cancer ◽

Clinicopathologic Features

Download Full-text

Genomic characterization of high-risk non-muscle invasive bladder cancer

Oncotarget ◽

10.18632/oncotarget.12661 ◽

2016 ◽

Vol 7 (46) ◽

pp. 75176-75184 ◽

Cited By ~ 33

Author(s):

Joshua J. Meeks ◽

Benedito A. Carneiro ◽

Sachin G. Pai ◽

Daniel T. Oberlin ◽

Alfred Rademaker ◽

...

Keyword(s):

Bladder Cancer ◽

High Risk ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Genomic Characterization ◽

Muscle Invasive

Download Full-text

Genomic Characterization of Severe Acute Respiratory Syndrome-Related Coronavirus in European Bats and Classification of Coronaviruses Based on Partial RNA-Dependent RNA Polymerase Gene Sequences

Journal of Virology ◽

10.1128/jvi.00650-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11336-11349 ◽

Cited By ~ 172

Author(s):

Jan Felix Drexler ◽

Florian Gloza-Rausch ◽

Jörg Glende ◽

Victor Max Corman ◽

Doreen Muth ◽

...

Keyword(s):

Amino Acid ◽

Severe Acute Respiratory Syndrome ◽

Surface Expression ◽

Emerging Viruses ◽

Reading Frame ◽

High Frequencies ◽

Nyctalus Leisleri ◽

Genomic Characterization

ABSTRACT Bats may host emerging viruses, including coronaviruses (CoV). We conducted an evaluation of CoV in rhinolophid and vespertilionid bat species common in Europe. Rhinolophids carried severe acute respiratory syndrome (SARS)-related CoV at high frequencies and concentrations (26% of animals are positive; up to 2.4 × 108 copies per gram of feces), as well as two Alphacoronavirus clades, one novel and one related to the HKU2 clade. All three clades present in Miniopterus bats in China (HKU7, HKU8, and 1A related) were also present in European Miniopterus bats. An additional novel Alphacoronavirus clade (bat CoV [BtCoV]/BNM98-30) was detected in Nyctalus leisleri. A CoV grouping criterion was developed by comparing amino acid identities across an 816-bp fragment of the RNA-dependent RNA polymerases (RdRp) of all accepted mammalian CoV species (RdRp-based grouping units [RGU]). Criteria for defining separate RGU in mammalian CoV were a >4.8% amino acid distance for alphacoronaviruses and a >6.3% distance for betacoronaviruses. All the above-mentioned novel clades represented independent RGU. Strict associations between CoV RGU and host bat genera were confirmed for six independent RGU represented simultaneously in China and Europe. A SARS-related virus (BtCoV/BM48-31/Bulgaria/2008) from a Rhinolophus blasii (Rhi bla) bat was fully sequenced. It is predicted that proteins 3b and 6 were highly divergent from those proteins in all known SARS-related CoV. Open reading frame 8 (ORF8) was surprisingly absent. Surface expression of spike and staining with sera of SARS survivors suggested low antigenic overlap with SARS CoV. However, the receptor binding domain of SARS CoV showed higher similarity with that of BtCoV/BM48-31/Bulgaria/2008 than with that of any Chinese bat-borne CoV. Critical spike domains 472 and 487 were identical and similar, respectively. This study underlines the importance of assessments of the zoonotic potential of widely distributed bat-borne CoV.

Download Full-text

Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2019.06.021 ◽

2019 ◽

Vol 37 (9) ◽

pp. 573.e19-573.e29 ◽

Cited By ~ 1

Author(s):

Vera Genitsch ◽

Attila Kollár ◽

Gillian Vandekerkhove ◽

Jennifer Blarer ◽

Marc Furrer ◽

...

Keyword(s):

Bladder Cancer ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Genomic Characterization ◽

Muscle Invasive

Download Full-text

Genomic characterization of variant histology muscle invasive bladder cancer (MIBC) to predict response to therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.e24290 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. e24290-e24290

Author(s):

Shilpa Gupta ◽

Badrinath R. Konety ◽

Elai Davicioni ◽

Ewan Gibb

Keyword(s):

Bladder Cancer ◽

Response To Therapy ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Genomic Characterization ◽

Variant Histology ◽

Muscle Invasive

Download Full-text

Repetitive DNA Hypomethylation in Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.2703.2703 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2703-2703

Author(s):

Sonia Fabris ◽

Valentina Bollati ◽

Laura Mosca ◽

Valeria Pegoraro ◽

Domenica Ronchetti ◽

...

Keyword(s):

Dna Methylation ◽

Multiple Myeloma ◽

Molecular Mechanisms ◽

Plasma Cells ◽

Human Cancer ◽

Wide Spectrum ◽

Rank Correlation ◽

Global Dna Methylation ◽

Dna Hypomethylation ◽

Alu Elements

Abstract Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells characterized by a wide spectrum of genetic and epigenetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear elements-1 (LINE-1) and Alu repetitive elements (approximately 500.000 and 1.4 million in the human genome) has been associated with chromosomal instability. Additionally, satellite alfa DNA (SAT-alpha DNA) hypomethylation has been reported to be associated to karyotypic instability in human cancer, possibly playing a role in centromere function. So far, the LINE-1/Alu and centromeric SAT-alpha DNA methylation patterns have not been investigated in the context of the different clinical and molecular MM subtypes. Global DNA methylation changes were investigated in a panel of 53 newly diagnosed, untreated MMs, 7 plasma cell leukemias (PCL) and 11 healthy subjects as controls. DNA was extracted from purified plasma cells, treated with bisulfite and analyzed by bisulfite-PCR and Pyrosequencing. Methylation of LINE-1 and Alu elements was shown to correlate with total 5mC content and thus used to estimate global DNA methylation. MMs showed a decrease of Alu (21.1%) and LINE-1 (70.0%) methylation average levels compared with controls (25.2% and 79.5% respectively). Lower median methylation levels were also found in centromeric SAT-alpha DNA of MMs (77.95%) compared to controls (89.5%). The median methylation level of PCLs was lower than MMs (16.7% versus 21.1% for Alu; 45.5% versus 70.0% for LINE-1; and 33.3% versus 77.9% for SATalpha DNA). Notably, a statistically significant association between SAT-alpha DNA and LINE-1 methylation (Spearman’s rank correlation, ρ = 0.94; P < 0.001) was found in MM. The comparison between methylation pattern and different molecular MM subgroups by means of non parametric tests, revealed that LINE-1 and SAT-alpha DNA methylation was significantly lower in the nonhyperdiploid versus hyperdiploid (HD) tumors (P = 0.01 and 0.02 respectively). Alu and SAT-alpha were significantly lower in the MMs with t(4;14) (P = 0.02 and 0.004 respectively). Finally, in the context of translocation/cyclin D (TC) classification, a statistically significant differences inside the five different groups were found for SAT-alpha DNA methylation (P = 0.008, Kruskal-Wallis test). These findings may provide insights into the molecular mechanisms of MM pathogenesis and suggest that our approach may contribute toward a more exhaustive stratification of the disease.

Download Full-text

Endoscopic spectrum and practical classification of small bowel gastrointestinal stromal tumors (GISTs) detected during double-balloon enteroscopy

Endoscopy International Open ◽

10.1055/a-1341-0404 ◽

2021 ◽

Vol 09 (04) ◽

pp. E507-E512

Author(s):

Alvaro Martinez-Alcalá ◽

Lucía C. Fry ◽

Thomas Kröner ◽

Shajan Peter ◽

Carlo Contreras ◽

...

Keyword(s):

Small Bowel ◽

Wide Spectrum ◽

Case Series ◽

Normal Mucosa ◽

Tumor Characteristics ◽

Double Balloon Enteroscopy ◽

Endoscopic Characteristics

Abstract Background and study aims Information about the endoscopic characterization of small bowel gastrointestinal tumors (GISTs) is limited. The aim of this case study was to describe the endoscopic spectrum of small bowel GISTs and to present a practical classification. Patients and methods Observational, retrospective, consecutive case series of patients with small bowel GIST. Results A total of 10 small bowel GISTs were found in patients (6 male, 4 female, mean age 52 years, range 28 to 68).). All patients presented with obscure gastrointestinal bleeding (overt, n = 8, occult, n = 2). Most GISTs were present in the proximal or middle small bowel (n = 7). The endoscopic tumor characteristics could be categorized as follows: submucosal round (n = 4), submucosal sessile (n = 2), and invasive/penetrating) (n = 4). The mucosa overlying the tumor was normal (n = 4), grooved (n = 3) or frankly ulcerated (n = 3). Tumor size ranged from 8 mm to 50 mm. Biopsy was negative in all patients with normal mucosa but showed tumor in all patients with ulcerations. Regardless of biopsy results, all patients were sent for surgery. Nine resections were carried out. One patient refused surgery. There were no complications of endoscopy in this cohort. Conclusion Our series shows that GISTs have a wider spectrum of endoscopic characteristics than previously described. The round type with normal overlying mucosa was equally prevalent as the grooved or ulcerated variant. Endoscopists should be aware of this wide spectrum of presentation of small bowel GIST.

Download Full-text