scholarly journals Non-invasive detection of bladder cancer through the analysis of driver gene mutations and aneuploidy

2017 ◽  
Author(s):  
Simeon Springer ◽  
Maria Del Carmen Rodriguez Pena ◽  
Lu Li ◽  
Christopher Douville ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
At Risk ◽  
Bladder Cancer ◽  
Gene Mutations ◽  
Urine Samples ◽  
Driver Gene ◽  
Low Grade ◽  
Invasive Approach ◽  
Non Invasive ◽  
Patients At Risk ◽  
Copy Number Changes

AbstractCurrent non-invasive approaches for bladder cancer (BC) detection are suboptimal. We report the development of non-invasive molecular test for BC using DNA recovered from cells shed into urine. This “UroSEEK” test incorporates assays for mutations in 11 genes and copy number changes on 39 chromosome arms. We first evaluated 570 urine samples from patients at risk for BC (microscopic hematuria or dysuria). UroSEEK was positive in 83% of patients that developed BC, but in only 7% of patients who did not develop BC. Combined with cytology, 95% of patients that developed BC were positive. We then evaluated 322 urine samples from patients soon after their BCs had been surgically resected. UroSEEK detected abnormalities in 66% of the urine samples from these patients, sometimes up to 4 years prior to clinical evidence of residual neoplasia, while cytology was positive in only 25% of such urine samples. The advantages of UroSEEK over cytology were particularly evident in low-grade tumors, wherein cytology detected none while UroSEEK detected 67% of 49 cases. These results establish the foundation for a new, non-invasive approach to the detection of BC in patients at risk for initial or recurrent disease.

scholarly journals Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Simeon U Springer ◽  
Chung-Hsin Chen ◽  
Maria Del Carmen Rodriguez Pena ◽  
Lu Li ◽  
Christopher Douville ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Gene Mutations ◽  
Driver Gene ◽  
Low Grade ◽  
Invasive Approach ◽  
Non Invasive ◽  
Genetic Abnormalities ◽  
Patients At Risk ◽  
Upper Tract Urothelial Cancer ◽  
Copy Number Changes

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.

scholarly journals Epigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2719
Author(s):  
Alba Loras ◽  
Cristina Segovia ◽  
José Luis Ruiz-Cerdá
Keyword(s):  
Bladder Cancer ◽  
Cancer Biology ◽  
Metabolic Regulation ◽  
Tumor Development ◽  
Dna Methyltransferases ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Invasive Approach ◽  
Non Invasive

Bladder cancer (BC) represents a clinical, social, and economic challenge due to tumor-intrinsic characteristics, limitations of diagnostic techniques and a lack of personalized treatments. In the last decade, the use of liquid biopsy has grown as a non-invasive approach to characterize tumors. Moreover, the emergence of omics has increased our knowledge of cancer biology and identified critical BC biomarkers. The rewiring between epigenetics and metabolism has been closely linked to tumor phenotype. Chromatin remodelers interact with each other to control gene silencing in BC, but also with stress-inducible factors or oncogenic signaling cascades to regulate metabolic reprogramming towards glycolysis, the pentose phosphate pathway, and lipogenesis. Concurrently, one-carbon metabolism supplies methyl groups to histone and DNA methyltransferases, leading to the hypermethylation and silencing of suppressor genes in BC. Conversely, α-KG and acetyl-CoA enhance the activity of histone demethylases and acetyl transferases, increasing gene expression, while succinate and fumarate have an inhibitory role. This review is the first to analyze the interplay between epigenome, metabolome and cell signaling pathways in BC, and shows how their regulation contributes to tumor development and progression. Moreover, it summarizes non-invasive biomarkers that could be applied in clinical practice to improve diagnosis, monitoring, prognosis and the therapeutic options in BC.

scholarly journals Diagnostic Performance of Oncuria™, a Urinalysis Test for Bladder Cancer

2021 ◽  
Author(s):  
Yosuke Hirasawa ◽  
Ian Pagano ◽  
Runpu Chen ◽  
Yijun Sun ◽  
Yunfeng Dai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Diagnostic Performance ◽  
Clinical Laboratory ◽  
Demographic Data ◽  
Roc Curves ◽  
Low Grade ◽  
Linear Discriminant ◽  
Non Invasive ◽  
Diagnostic Panel ◽  
Parallel Measurement

Abstract Background: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with bladder cancer. The identification of multiplex molecular signatures associated with disease has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis and monitoring. Methods: To evaluate the performance of Oncuria™, a multiplex immunoassay for bladder detection in voided urine samples. The test was evaluated in a multi-institutional cohort of 362 prospectively collected subjects presenting for bladder cancer evaluation. The parallel measurement of 10 biomarkers (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) was performed in an independent clinical laboratory. The ability of the test to identify patients harboring bladder cancer was assessed. Bladder cancer status was confirmed by cystoscopy and tissue biopsy. The association of biomarkers and demographic factors was evaluated using linear discriminant analysis (LDA) and predictive models were derived using supervised learning and cross-validation analyses. Diagnostic performance was assessed using ROC curves.Results: The combination of the 10 biomarkers provided an AUROC 0.93 [95% CI: 0.87 – 0.98], outperforming any single biomarker. The addition of demographic data (age, sex, and race) into a hybrid signature improved the diagnostic performance AUROC 0.95 [95% CI: 0.90 – 1.00]. The hybrid signature achieved an overall sensitivity of 0.93, specificity of 0.93, PPV of 0.65 and NPV of 0.99 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, MIBC and NMIBC were 0.94, 0.89, 0.97 and 0.93, respectively. Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of bladder cancer patients and controls. The multiplex Oncuria™ test can achieve the efficient and accurate detection and monitoring of bladder cancer in a non-invasive patient setting.

scholarly journals Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 686 ◽  
Author(s):  
Alba Loras ◽  
Cristian Suárez-Cabrera ◽  
M. Carmen Martínez-Bisbal ◽  
Guillermo Quintás ◽  
Jesús M. Paramio ◽  
...  
Keyword(s):  
Amino Acids ◽  
Bladder Cancer ◽  
Tricarboxylic Acid Cycle ◽  
Tumor Biology ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Tissue Samples ◽  
Invasive Approach ◽  
Non Invasive ◽  
Angle Spinning

Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. BC and control tissue samples (n = 44) from the same patients were analyzed by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance and microarrays techniques. Besides, urinary profiling study (n = 35) was performed in the same patients to identify a metabolomic profile, linked with BC tissue hallmarks, as a potential non-invasive approach for BC diagnosis. The metabolic profile allowed for the classification of BC tissue samples with a sensitivity and specificity of 100%. The most discriminant metabolites for BC tissue samples reflected alterations in amino acids, glutathione, and taurine metabolic pathways. Transcriptomic data supported metabolomic results and revealed a predominant downregulation of metabolic genes belonging to phosphorylative oxidation, tricarboxylic acid cycle, and amino acid metabolism. The urinary profiling study showed a relation with taurine and other amino acids perturbed pathways observed in BC tissue samples, and classified BC from non-tumor urine samples with good sensitivities (91%) and specificities (77%). This urinary profile could be used as a non-invasive tool for BC diagnosis and follow-up.

scholarly journals Quality and cost assessment of Canadian Urological Association microscopic hematuria guidelines in clinical practice: Turning urine into gold

2019 ◽  
Vol 13 (10) ◽  
Author(s):  
Mark A. Assmus ◽  
D. Beyer ◽  
Joan Hanks ◽  
Mathew Estey ◽  
Keith F. Rourke ◽  
...  
Keyword(s):  
Guideline Adherence ◽  
Healthcare Costs ◽  
Patient Characteristics ◽  
Urine Samples ◽  
Microscopic Hematuria ◽  
Low Grade ◽  
Normal Cytology ◽  
Non Invasive ◽  
Database Evaluation ◽  
Alberta Health

Introduction: Asymptomatic microscopic hematuria (AMH) is defined in the Canadian Urological Association (CUA) guidelines as >2 red blood cells (RBCs) per high-powered field (hpf). Our objective is to evaluate guideline adherence for AMH at our centre. Secondarily, we aim to identify areas of the guideline that can be optimized. Methods: We retrospectively reviewed 875 consecutive adults referred to two urologists for hematuria from June 2010–2016. Patient characteristics, risk factors, and outcomes were added to an encrypted REDCap database. Evaluation of microscopic hematuria reporting was performed by analyzing 681 urine samples reported as 1–5 RBC/hpf. Healthcare costs were obtained from Alberta Health Services (AHS), Data Integration and Management Repository (DIMR), and Alberta Society of Radiologists (ASR). Results: Of the 875 patients referred with hematuria, 400 had AMH. Overall, 96.5% completed evaluation consistent with the CUA guideline. The incidence of pathology requiring surgical intervention was 21/400 (5%), with a 0.8% rate (3/400) of urothelial cell carcinoma (UCC) (non-invasive, low-grade). No malignancy was found in non-smokers with normal cytology, normal imaging and <50 RBC/hpf; 44% had AMH in the 1–5 RBCs/hpf range. Only 41% (279/681) of urine samples categorized as 1–5 RBCs/hpf had guideline-defined microscopic hematuria. By changing local microscopic hematuria reporting to differentiate 1–2 and 3–5 RBCs/hpf, we estimate $745 000 in annual savings. Conclusions: At our centre, CUA AMH guideline adherence is high. We did not find malignancy in non-smokers with normal cytology, imaging, and <50 RBC/hpf. We identified and changed regional microscopic hematuria reporting to fit the CUA definition, eliminating unnecessary investigations and healthcare costs.

1779 SURVEILLANCE GUIDELINES FOR LOW GRADE NON-INVASIVE BLADDER CANCER: A COST COMPARISON

2012 ◽  
Vol 187 (4S) ◽  
Author(s):  
Ian Udell ◽  
Raj Kurpad ◽  
Angela Smith ◽  
Michael Woods ◽  
Eric Wallen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cost Comparison ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
Non Invasive

Non Invasive Assessment of Hepatic Fibrosis by Measurement of Liver Stiffness in Post Transfusional Iron Overload: Preliminary Results in 15 Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3740-3740
Author(s):  
T. Mirault ◽  
D. Lucidarme ◽  
B. Turlin ◽  
Y. Deugnier ◽  
P. Brissot ◽  
...  
Keyword(s):  
At Risk ◽  
Liver Fibrosis ◽  
Iron Overload ◽  
Predictive Value ◽  
Liver Stiffness ◽  
Liver Iron ◽  
Preliminary Results ◽  
Non Invasive ◽  
Patients At Risk ◽  
Severe Fibrosis

Abstract Background: The prognosis of liver iron overload is highly dependent on liver iron content (LIC) and the extent of liver fibrosis. Liver biopsy is the invasive reference method for fibrosis evaluation but with several limitations. Non-invasive biological methods (FibroTest, APRI) are not applicable in blood diseases. Transient elastography (TE) is a new non-invasive and rapid bedside method used to measure liver stiffness.This technique has been extensively studied with success in evaluation of liver fibrosis in HCV infection (Ziol, Hepatology 2005; Castera, Gastroenterology 2005). Until now, no data are available on evaluation of liver fibrosis by TE in highly transfused patients with iron overload. Methods: We assessed liver stiffness (kPa) by elastography measurement (Fibroscan; Echosens, Paris, France). Ishak’s and Metavir’s scales were used to stage fibrosis and hepatitis activity; LIC was measured by atomic absorption spectometry in a central laboratory (Rennes, France) and by MRI procedure according to Gandon (Lancet 2004). Cardiac MRI T2* (indirect estimation of iron heart content) was also measured by MRI according to Anderson (Eur Heart J 2001). Serum ferritin level and HCV serology were assayed in all cases. Correlation statistical analysis used Spearman’s Rho and Pearson tests and mean comparisons were done by a non-parametric Mann-Whitney test. Results: 15 liver samples (weight >1mg except 1) from monthly transfused patients (13 major beta Thalassemia, 1 sickle cell disease, 1 myelodysplastic syndrome) were analyzed. Median age was 37 years (7–75). Histological results were: 3 cirrhosis (METAVIR F=4 (F4), or Ishak’s Staging =6 (IS6)) among 5 patients with severe fibrosis (F3,F4) or (IS4-6) and 10 patients with no or mild fibrosis (F0-2) or (IS0-3). Mean ferritin was 2579 ng/ml CI 95% [1372–3786]. 2 patients were HCV positive. Correlation between LIC and ferritin was 0.82 (p<0,05); between LIC and MRI LIC: 0.88 (p<0,05); LIC and MRI Heart T2*: 0.72(p<0,05); METAVIR F score and Ishak’s grading score: 0.86 (p<0,05). A correlation was also observed between METAVIR F and elastography: 0.60(p<0,05); and mean values of elastography were significally different in patients with severe fibrosis: 9.1kPa CI95% [4.5–13.7] vs 5.9kPa CI95% [4.6–7.2] in those without sever fibrosis (p<0,05) (fig). A value of elastography above 6.25kPa (Se=80%; Sp=70%; AUROC=0.820) identified patients at risk for severe fibrosis (F3,F4 or IS 4–6) (Negative Predictive Value = 88%; Positive Predictive Value = 57%). Conclusion: A significant correlation between Metavir Fibrosis scale and elastography values was found. This new non-invasive method would be helpful to evaluate liver fibrosis and to determine patients who could avoid invasive procedures in particular in regularly transfused low risk myelodysplastic patients at risk of bleeding due to abnormal platelet function. These preliminary results will have to be confirmed in a larger population. Figure Figure

Use of next-generation deep sequencing to improve FGFR3 mutation detection in the urine of patients with bladder cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 289-289
Author(s):  
John M. Millholland ◽  
Shuqiang Li ◽  
Cecilia A. Fernandez ◽  
Anthony P. Shuber
Keyword(s):  
Bladder Cancer ◽  
Deep Sequencing ◽  
Mutation Detection ◽  
Amplicon Sequencing ◽  
Urine Samples ◽  
Next Generation ◽  
High Background ◽  
Non Invasive ◽  
Fgfr3 Mutation ◽  
Fgfr3 Mutations

289 Background: FGFR3 mutations have been identified in ∼60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ∼30% of the urine samples, which is < 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ∼67%, near the expected detection if every mutation found in tissue could be detected in urine. Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Taqman probes were used to determine if sufficient DNA was present in each sample. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation. Results: Urine samples from 29 patients with stage Ta bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Of the 29 samples, 2 did not have sufficient DNA for analysis by sequencing. Using ultra-deep amplicon sequencing, 18 out of 27 (66.7%) were positive for FGFR3 mutations, while only 3 out of 27 (11.1%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05%. The sensitivity achieved using deep sequencing approximates the FGFR3 mutations observed in tissue. Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at < 1% of the sample and suggests > 90% concordance with the expected mutations in Ta tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.

An accurate, non-invasive approach to diagnose Cushing’s syndrome in at-risk populations

Steroids ◽  
2013 ◽  
Vol 78 (5) ◽  
pp. 476-482 ◽  
Author(s):  
Estela M.L. Cardoso ◽  
Alejandro L. Arregger ◽  
Gloria Monardes ◽  
Liliana N. Contreras
Keyword(s):  
At Risk ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Invasive Approach ◽  
Non Invasive ◽  
At Risk Populations
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