scholarly journals Multi-Omics Analysis Identifies the Heterogeneity and Prognosis in Bladder Cancer

2021 ◽  
Author(s):  
Wenchao Ma ◽  
Cheng Li ◽  
Yuchao Liu ◽  
Wentao Zhang ◽  
Yadong Guo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
High Risk ◽  
Copy Number ◽  
Low Risk ◽  
Biological Behavior ◽  
Methylation Data ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Risk Patients

Abstract Background The multi-omics integrated analysis can help researchers understand the biological behavior of bladder cancer(BCa) in a more systematic and comprehensive manner, and further provide new clues for finding valuable tumor markers and therapeutic targets. Methods In this study, we applied the DNA methylation data to construct a prognosis classifier and stratified the BCa patients into high- and low-risk subtype. The differences of transcriptome, single nucleotide variants and copy number variations between two subgroups were explored for finding the changes of molecular mechanism. Results With 18 pairs DNA methylation samples, ten differentially methylated positions(DMPs) were identified and applied to evaluate the risk score of each sample. Kaplan-Meier survival analysis displayed that BCa patients with high risk had a poor prognosis than the lower(p<0.0001). In transcriptome analysis, many immune related pathways and biological process changed between high- and low-risk patients. The results also displayed that naive B cells, plasma cells, CD8+ T cells and T cell regulatory(Tregs) infiltrated less in high-risk patients and these patients were less sensitive to immunotherapy and chemotherapy. As for single nucleotide variants, we found that TP53, CDKN1A, STAG2 and other genes were more frequently mutated in high-risk BCa patients. Only copy number variation in high-risk patients were displayed for the limitation of TCGA data. Conclusions The high- and low-risk patients identified by DNA methylation data of bladder cancer were significant different in survival. The comprehensive comparison of multi-omics data between subgroups can help clinicians find the heterogeneity of tumor biological behavior and contribute to precision treatment in bladder cancer.

Does “low risk” muscle invasive bladder cancer actually exist?

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 308-308
Author(s):  
Eugene J. Pietzak ◽  
S. Bruce Malkowicz ◽  
Thomas J. Guzzo
Keyword(s):  
Risk Factors ◽  
Bladder Cancer ◽  
High Risk ◽  
Low Risk ◽  
Risk Patients ◽  
Variant Histology ◽  
Mixed Histology ◽  
Muscle Invasive ◽  
Tumor Upstaging ◽  
Mixed Variant

308 Background: Despite level one evidence demonstrating improved survival with neoadjuvant chemotherapy (NAC), studies suggest that many eligible patients with muscle invasive bladder cancer (MIBC) never receive it prior to radical cystectomy (RC). Our objective was to determine if the absence of known pre-operative risk factors can indeed stratify for low risk of extravesical disease with RC alone. Methods: We identified consecutive NAC-naive patients with clinical stage cT2N0M0 urothelial type bladder cancer treated with RC at our center. cT2 patients with either hydronephrosis, transurethral resection (TUR) specimens containing lymphovascular invasion (LVI), or mixed variant histology were grouped as high risk. Clinicopathologic and survival outcomes were compared to cT2 patients without these adverse features, who were grouped as low risk. Results: Of 251 cT2 patients, 119 (47.4%) were high risk [LVI=31, hydronephrosis=69, mixed histology=54; ≥2 risk factors=70]. High and low risk cohorts did not differ in age, gender, race, BMI, smoking, co-morbidities, prior intravescial therapy, or treatment delay. At time of RC, high risk patients more often had lymph node metastasis (38.6% v. 26.7% p=0.04) & tumor upstaging to pT3/4 (53.7% v. 40.2 p<0.001), with significantly less achieving pT0 (2.5% v. 12.1% p=0.004). There was no difference in adjuvant chemotherapy rates (26.4% v. 25% p=0.8). Two and five year cancer-specific survival (CSS) was 84.8% and 62.3% for low risk patients, but only 59.5% and 42% for high risk patients (p=0.008), with competing risk analysis revealing worse bladder cancer specific mortality (BCSM) (sub HR=2.08 [95%CI=1.36 – 3.2]). Odds Ratio for BCSM was 1.29 (95%CI=0.68-2.5) if one risk factor was present, & 3.2 (95%CI=1.7-5.8) if two risk factors. Only hydronephrosis (2.2 [95%CI=1.2-4.2]) and mixed histology (2.4 [95%CI=1.2-4.8]) were independently associated with worse BCSM on multi-variable analysis. Conclusions: Good cancer control is provided by RC alone to many patients with cT2 MIBC without adverse risk factors, particularly if hydronephrosis & mixed variant histology is absent. However, tumor upstaging and lymph node involvement is not trivial even in low risk patients, which must be included in informed decision making on NAC.

scholarly journals Advancements in Intravesical Chemotherapy in Non-Muscle Invasive Bladder cancer

2021 ◽  
Author(s):  
Ankur Mittal ◽  
Vikas Kumar Panwar ◽  
Gurpremjit Singh
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Low Risk ◽  
Intravesical Chemotherapy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Risk Patients ◽  
Bcg Failure ◽  
Significant Stage ◽  
Muscle Invasive

The treatment for non-muscle-invasive bladder cancer is transurethral resection of bladder cancer followed by intravesical chemotherapy or BCG. There have been various advancements in low risk, intermediate risk, high risk, and BCG failure cases of non-muscle invasive bladder cancer. There has been increased research on hyperthermia and intravesical chemotherapy, new agents like apaziquone, use of gemcitabine in low-risk cases, and combination chemotherapy in cases of BCG failure. Combining docetaxel and gemcitabine has taken a significant stage because of BCG shortage in some parts of the world. This chapter will discuss the latest advancements in intravesical chemotherapy in low, intermediate, and high-risk patients.

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

scholarly journals Echocardiography and EuroSCORE II for the stratification of low-gradient severe aortic stenosis and preserved left ventricular ejection fraction

2021 ◽  
Author(s):  
Yan Fan ◽  
Hong Shen ◽  
Brandon Stacey ◽  
David Zhao ◽  
Robert J. Applegate ◽  
...  
Keyword(s):  
High Risk ◽  
Left Ventricular Ejection Fraction ◽  
Risk Group ◽  
Severe Aortic Stenosis ◽  
Left Ventricular ◽  
High Risk Group ◽  
Low Risk ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Risk Patients

AbstractThe purpose of this study was to explore the utility of echocardiography and the EuroSCORE II in stratifying patients with low-gradient severe aortic stenosis (LG SAS) and preserved left ventricular ejection fraction (LVEF ≥ 50%) with or without aortic valve intervention (AVI). The study included 323 patients with LG SAS (aortic valve area ≤ 1.0 cm2 and mean pressure gradient < 40 mmHg). Patients were divided into two groups: a high-risk group (EuroSCORE II ≥ 4%, n = 115) and a low-risk group (EuroSCORE II < 4%, n = 208). Echocardiographic and clinical characteristics were analyzed. All-cause mortality was used as a clinical outcome during mean follow-up of 2 ± 1.3 years. Two-year cumulative survival was significantly lower in the high-risk group than the low-risk patients (62.3% vs. 81.7%, p = 0.001). AVI tended to reduce mortality in the high-risk patients (70% vs. 59%; p = 0.065). It did not significantly reduce mortality in the low-risk patients (82.8% with AVI vs. 81.2%, p = 0.68). Multivariable analysis identified heart failure, renal dysfunction and stroke volume index (SVi) as independent predictors for mortality. The study suggested that individualization of AVI based on risk stratification could be considered in a patient with LG SAS and preserved LVEF.

scholarly journals Accuracy of upper endoscopies with random biopsies to identify patients with gastric premalignant lesions who can safely be exempt from surveillance

2021 ◽  
Vol 24 (3) ◽  
pp. 680-690
Author(s):  
Michiel C. Mommersteeg ◽  
Stella A. V. Nieuwenburg ◽  
Wouter J. den Hollander ◽  
Lisanne Holster ◽  
Caroline M. den Hoed ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
High Risk ◽  
Low Risk ◽  
Premalignant Lesions ◽  
High Risk Patients ◽  
European Guidelines ◽  
Progression Of Disease ◽  
Risk Patients ◽  
Progression Risk

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.

scholarly journals A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

2021 ◽  
Vol 22 (3) ◽  
pp. 1075
Author(s):  
Luca Bedon ◽  
Michele Dal Bo ◽  
Monica Mossenta ◽  
Davide Busato ◽  
Giuseppe Toffoli ◽  
...  
Keyword(s):  
Machine Learning ◽  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Progression Free Survival ◽  
Low Risk ◽  
Functional Enrichment ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Of Progression ◽  
Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

scholarly journals Evaluation of affinity-based genome-wide DNA methylation data: Effects of CpG density, amplification bias, and copy number variation

2010 ◽  
Vol 20 (12) ◽  
pp. 1719-1729 ◽  
Author(s):  
M. D. Robinson ◽  
C. Stirzaker ◽  
A. L. Statham ◽  
M. W. Coolen ◽  
J. Z. Song ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number Variation ◽  
Copy Number ◽  
Methylation Data ◽  
Amplification Bias ◽  
Genome Wide ◽  
Number Variation

scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

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