Genetic alterations in bladder cancer

Studying bladder cancer molecular biology revealed the presence of genetic alterations. So, detection of molecular biomarkers that help in monitoring the disease, evaluating the prognosis of the patients, and their response to therapy is needed. In this study, we investigated the expression and the prognostic significance of SATB-1 and ERBB2 mRNA and protein by quantitative RT-PCR and immunohistochemical analysis in urothelial bladder cancer cases and the surrounding normal bladder tissue. The correlations between the expression of both markers and the clinicopathological parameters were performed with further analysis of the correlation between the expression of SATB-1 and ERBB2. Compared to control, the expression of SATB-1 and ERBB2 mRNA and protein in cancer tissues were significantly up-regulated (p< 0.05). Also, a positive correlation between both markers was found (r= 0.53, p< 0.001). Moreover, elevated levels of both markers were significantly associated with the stage, lymph node involvement at both mRNA and protein levels (p< 0.001). In conclusion, there is a clinical significance of SATB-1 and ERBB2 as potential biomarkers for predicting bladder cancer patients of aggressive behavior and poor prognosis.

Download Full-text

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

Genome Medicine ◽

10.1186/s13073-020-00781-y ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Ming-Jun Shi ◽

Xiang-Yu Meng ◽

Jacqueline Fontugne ◽

Chun-Long Chen ◽

François Radvanyi ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Target Genes ◽

Genetic Alterations ◽

Driver Mutations ◽

Joint Analysis ◽

Tumour Suppressor Genes ◽

Loss Of Function ◽

Aryl Hydrocarbon ◽

Hotspot Mutations

Abstract Background APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. Conclusions Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.

Download Full-text

Erdafitinib: A novel therapy for FGFR-mutated urothelial cancer

American Journal of Health-System Pharmacy ◽

10.1093/ajhp/zxz329 ◽

2020 ◽

Vol 77 (5) ◽

pp. 346-351 ◽

Cited By ~ 2

Author(s):

Kiera Roubal ◽

Zin W Myint ◽

Jill M Kolesar

Keyword(s):

Bladder Cancer ◽

Urothelial Cancer ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Clinical Effectiveness ◽

Genetic Alterations ◽

Novel Therapy ◽

Days Of Therapy ◽

Phase 2 Clinical Trial ◽

Gene Alterations

Abstract Purpose To provide an overview of fibroblast growth factor receptor (FGFR) gene alterations and the pharmacology, clinical effectiveness, dosage and administration, cost, and place in therapy of erdafitinib in bladder cancer. Summary Erdafitinib (Balversa, Janssen Pharmaceuticals) is a novel pan-FGFR inhibitor recently approved for the treatment of patients with advanced urothelial cancer with specific FGFR genetic alterations who have received at least one prior platinum-containing regimen. Erdafitinib binding to the FGFR2 and FGFR3 receptors inhibits FGF activity, resulting in cell death. Erdafitinib is available in tablet form, and the current recommended daily dosing is 8 mg, with dose escalation to 9 mg after 14 to 21 days of therapy if tolerated. A phase 2 clinical trial demonstrated that patients who received erdafitinib experienced on average 5.5 months of progression-free survival (95% confidence interval [CI], 4.2-6.0 months). In addition, 40% (95% CI, 31-50%) of patients responded to erdafitinib therapy. Patients receiving erdafitinib therapy should be monitored specifically for elevations in serum phosphate levels and changes in vision. Other adverse effects include anemia, thrombocytopenia, and electrolyte abnormalities. Conclusion Erdafitinib is the first small-molecule FGFR inhibitor approved for use in advanced bladder cancer.

Download Full-text

Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses

The Journal of Pathology ◽

10.1002/path.1259 ◽

2002 ◽

Vol 199 (1) ◽

pp. 50-57 ◽

Cited By ~ 89

Author(s):

EC Obermann ◽

K Junker ◽

R Stoehr ◽

W Dietmaier ◽

D Zaak ◽

...

Keyword(s):

Bladder Cancer ◽

Genetic Alterations

Download Full-text

Genetic alterations and biological pathways in human bladder cancer pathogenesis

Urologic Oncology Seminars and Original Investigations ◽

10.1016/s1078-1439(00)00079-x ◽

2000 ◽

Vol 5 (5) ◽

pp. 191-203 ◽

Cited By ~ 47

Author(s):

Catherine A Reznikoff ◽

Somdatta Sarkar ◽

Knut P Jülicher ◽

Melissa S Burger ◽

Jairaj A Puthenveettil ◽

...

Keyword(s):

Bladder Cancer ◽

Genetic Alterations ◽

Biological Pathways ◽

Human Bladder Cancer ◽

Human Bladder ◽

Cancer Pathogenesis

Download Full-text

Targeting ERBB2 mutations in urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.354 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 354-354

Author(s):

Francois Audenet ◽

Sumit Isharwal ◽

Maria E. Arcila ◽

Samuel Funt ◽

Jonathan E. Rosenberg ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Allele Frequency ◽

Kinase Inhibitors ◽

Hot Spot ◽

Genetic Alterations ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Stage Disease ◽

Muscle Invasive

354 Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]

Download Full-text

Detection of genetic alterations at chromosomes 3, 7, 9p21, and 17 with multitarget fish in bladder washings as noninvasive diagnostic tool for bladder cancer

European Urology Supplements ◽

10.1016/s1569-9056(02)80301-3 ◽

2002 ◽

Vol 1 (1) ◽

pp. 79

Author(s):

Marieta Toma ◽

Martin Friedrich ◽

Stefan Hautmann

Keyword(s):

Bladder Cancer ◽

Diagnostic Tool ◽

Genetic Alterations

Download Full-text

Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPARγ

Cancers ◽

10.3390/cancers12123580 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3580

Author(s):

Dong Man Jang ◽

Jun Young Jang ◽

Hyun-Jung Kim ◽

Byung Woo Han

Keyword(s):

Bladder Cancer ◽

Ligand Binding ◽

Transcriptional Activity ◽

Molecular Mechanisms ◽

Genetic Alterations ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Differential Effects ◽

Tumor Microenvironments ◽

New Biomarkers

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been revealed to regulate tumor microenvironments. In particular, genetic alterations of PPARγ found in various cancers have been reported to play important roles in tumorigenesis by affecting PPARγ transactivation. In this study, we found that helix H3 of the PPARγ ligand-binding domain (LBD) has a number of sites that are mutated in cancers. To uncover underlying molecular mechanisms between helix H3 mutations and tumorigenesis, we performed structure‒function studies on the PPARγ LBDs containing helix H3 mutations found in cancers. Interestingly, PPARγ Q286E found in bladder cancer induces a constitutively active conformation of PPARγ LBD and thus abnormal activation of PPARγ/RXRα pathway, which suggests tumorigenic roles of PPARγ in bladder cancer. In contrast, other helix H3 mutations found in various cancers impair ligand binding essential for transcriptional activity of PPARγ. These data indicate that cancer-associated mutations clustered in helix H3 of PPARγ LBD exhibit differential effects in PPARγ-mediated tumorigenesis and provide a basis for the development of new biomarkers targeting tumor microenvironments.

Download Full-text