Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ preservation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16527-e16527
Author(s):  
Iver Nordentoft ◽  
Emil Christensen ◽  
Karin Birkenkamp-Demtröder ◽  
Sunil Deochand ◽  
Dillon Maloney ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Organ Preservation ◽  
Residual Disease ◽  
Detection Sensitivity ◽  
Precision Oncology ◽  
Response Measure ◽  
Non Invasive ◽  
Post Surgery ◽  
Genome Wide ◽  
Tumor Load

e16527 Background: Bladder cancer (BC) is the 9th most commonly diagnosed cancer worldwide and each year responsible for 165,000 deaths. Neoadjuvant combination chemotherapy, followed by radical cystectomy, is used for the management of localized muscle-invasive bladder cancer. One of the critical challenges in this therapeutic regimen is monitoring the tumor load to assess therapeutic efficacy – this is typically performed by assessing pathological downstaging in the cystectomy specimen. A high frequency of patients presents with T0N0 at cystectomy (no indication of residual disease), and consequently, it is vital to investigate organ preservation approaches to identify those patients who may qualify for bladder preservation. For precision oncology, we need to develop quantitative and non-invasive diagnostic methodologies to help the oncologist tailor the treatments to individual patients and monitor them for further clinical decision-making. Methods: Cell-free DNA (cfDNA) mutation detection has shown significant promise in its ability to monitor minimal residual disease and disease relapse by detection of cancer mutations in the peripheral blood. However, the combination of low tumor fraction and limited input material obtained from a typical plasma sample restricts the probability of detecting low metastatic burden in cfDNA through current deep targeted sequencing methods. Results: Here we present results from applying whole-genome sequencing (WGS) of cfDNA. We integrate a genome-wide mutation and copy number monitoring approach coupled with advanced signal processing and Artificial Intelligence (AI) for measuring the tumor load from low-input blood samples (̃1mL of plasma) with ultra-sensitive detection. The increased sensitivity allowed clinical detection of tumor fraction down to 8*10-5 and recurrence detection sensitivity achieving > 65% at the first two months post-surgery. The WGS cfDNA approach is being evaluated on a patient cohort of more than 50 bladder cancer patients with longitudinal plasma sampling during neoadjuvant chemotherapy (response measure), pre-cystectomy (complete response measure), and post-surgery (relapse monitoring). Conclusions: The results indicate the clinical potential of genome-wide mutation integration as an ultra-sensitive, non-invasive diagnostic method for bladder cancer clinical management and bladder organ preservation.

scholarly journals Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling

2019 ◽  
Vol 65 (7) ◽  
pp. 927-936 ◽  
Author(s):  
Timothy H T Cheng ◽  
Peiyong Jiang ◽  
Jeremy Y C Teoh ◽  
Macy M S Heung ◽  
Jacqueline C W Tam ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Copy Number ◽  
Bisulfite Sequencing ◽  
Residual Disease ◽  
Shallow Depth ◽  
Disease Stage ◽  
Low Grade ◽  
Multiple Time ◽  
Genome Wide ◽  
Tumor Load

Abstract BACKGROUND The current diagnosis and monitoring of bladder cancer are heavily reliant on cystoscopy, an invasive and costly procedure. Previous efforts in urine-based detection of bladder cancer focused on targeted approaches that are predicated on the tumor expressing specific aberrations. We aimed to noninvasively detect bladder cancer by the genome-wide assessment of methylomic and copy number aberrations (CNAs). We also investigated the size of tumor cell-free (cf)DNA fragments. METHODS Shallow-depth paired-end genome-wide bisulfite sequencing of urinary cfDNA was done for 46 bladder cancer patients and 39 cancer-free controls with hematuria. We assessed (a) proportional contribution from different tissues by methylation deconvolution, (b) global hypomethylation, (c) CNA, and (d) cfDNA size profile. RESULTS Methylomic and copy number approaches were synergistically combined to detect bladder cancer with a sensitivity of 93.5% (84.2% for low-grade nonmuscle-invasive disease) and a specificity of 95.8%. The prevalence of methylomic and CNAs reflected disease stage and tumor size. Sampling over multiple time points could assess residual disease and changes in tumor load. Muscle-invasive bladder cancer was associated with a higher proportion of long cfDNA, as well as longer cfDNA fragments originating from genomic regions enriched for tumor DNA. CONCLUSIONS Bladder cancer can be detected noninvasively in urinary cfDNA by methylomic and copy number analysis without previous knowledge or assumptions of specific aberrations. Such analysis could be used as a liquid biopsy to aid diagnosis and for potential longitudinal monitoring of tumor load. Further understanding of the differential size and fragmentation of cfDNA could improve the detection of bladder cancer.

scholarly journals Rapid Mass Spectrometric Diagnosis of Bladder Cancer via Urine Carbonyl Metabolic Fingerprints

2021 ◽  
Author(s):  
Zongxiu Nie ◽  
Yuze Li ◽  
Lixia Jiang ◽  
Zhenpeng Wang ◽  
Xiaohua Cao ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Point Of Care ◽  
Low Cost ◽  
Mass Spectrometric ◽  
Detection Sensitivity ◽  
Ionization Mass ◽  
Non Invasive ◽  
Diagnosis Method ◽  
Rapid Mass ◽  
Potential Biomarkers

Abstract The diagnosis of bladder cancer (BC) is currently based on cystoscopy, which is invasive and expensive. Here, we described a non-invasive, low-cost BC diagnosis method based on a desorption, separation, and ionization mass spectrometry platform (DSI-MS) that adopts N, N- Dimethylethylenediamine (DMED) as a differential labeling reagent. The DSI-MS platform avoids the interferences from intra- and/or inter-samples, while the DMED increases detection sensitivity and distinguishes carboxyl, aldehyde, and ketone groups from untreated samples. Carbonyl metabolic fingerprints of urine from 28 BC patients and 38 controls were portrayed and significant differences of some potential biomarkers were observed. The mechanisms of the changes have been discussed. Logistic regression (LR) was applied to discriminate BC from controls and an accuracy of 87% was achieved. We believe this patient-friendly method provides a hopeful approach for BC rapid point-of-care diagnostic.

scholarly journals Liquid Biopsy in Early Breast Cancer: A Preliminary Report

2020 ◽  
pp. 1-8
Author(s):  
Antonio Rulli ◽  
Antognelli Cinzia ◽  
Antonio Rulli ◽  
Covarelli Piero ◽  
Izzo Luciano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Early Stage ◽  
Dynamic Monitoring ◽  
Molecular Profile ◽  
Precision Oncology ◽  
Surgical Biopsy ◽  
Post Surgery ◽  
Genetic Landscape

Background: Liquid biopsy (LB) is a technique that utilizes circulating biomarkers from cancer patients to provide information regarding the genetic landscape of the cancer. LB is emerging as an alternative and complementary diagnostic and prognostic tool to surgical biopsy and is expected to provide the tool for the implementation of precision oncology in clinical settings. In fact, it may contribute to enhance understanding of tumor heterogeneity and permitting the dynamic monitoring of treatment responses and genomic variations. Thus, LB is a promising method for the management of cancer, including breast cancer (BC), whose incidence in Italy is progressively increasing. Previous studies focused mainly on patients with advanced-stage BC. In the present study we evaluated the number of circulating tumor cells (CTCs), the quantity of cell free tumor DNA (cftDNA) and the analysis of the mutational profile of DNA from CTCs (ctcDNA) and cftDNA in early stage BC patients. Methods: Matched pre- and post-surgery blood samples were collected from 47 early stage BC patients. CTCs enumeration was done using Isoflux system, molecular profile of ctcDNA and cftDNA was performed with the Spotlight 59 Panels kit on a MiSeq Illumina instrument. Results: Eighty percent of samples was CTCs-positive, while healthy controls were all CTCs-negative. Forty-four patients provided a pre-surgery and 21 post-surgery sample. By comparing the number of CTCs post-surgery with that of pre-surgery, we found that 66% of patients showed a decreased number of CTCs, 14% of patients continued to have the same number of CTCs, while, interestingly, 19% of patients showed an increased number of CTCs. Next Generation Sequencing (NGS) of ctcDNA and cftDNA showed that 52% of samples had mutations in 9 genes (TP53, CDKN2A, FBXW7, PTPN11, KRAS, NRAS, BRAF, IDH1, ALK) and in 5 genes (PIK3CA, APC ALK, KRAS, TSC1), respectively, with KRAS and ALK overlapping and TP53 being the most frequently mutated gene in ctcDNA analysis. Conclusions: LB could facilitate early detection of minimal residual disease, aiding in the initiation of adjuvant therapy to prevent recurrence and progression towards metastasis, enhance individualized treatment and longitudinal screening, thus improving the clinical management and outcome of patients with early BC.

Genome-wide identification of cell-free microRNAs in urine for non-invasive detection of bladder cancer

2017 ◽  
Vol 16 (11) ◽  
pp. e2939
Author(s):  
M. Stanik ◽  
J. Juráček ◽  
L. Radová ◽  
D. Macík ◽  
J. Doležel ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Non Invasive ◽  
Genome Wide

Post resection circulating residual disease monitoring in early stage lung and colorectal cancer patients using a circulating cell-free DNA assay with ultra-high accuracy and specificity.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23068-e23068
Author(s):  
Annie Maslan ◽  
Ariel Jaimovich ◽  
Narsi Rajagopalan ◽  
Michelle Tan ◽  
Stefanie Mortimer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Residual Disease ◽  
Early Stage ◽  
Tumor Resection ◽  
Background Rate ◽  
Lung Cancer Patients ◽  
Non Invasive ◽  
Post Surgery ◽  
Initial Recurrence

e23068 Background: Analysis of cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is a promising method for detecting and monitoring earlier stage cancers. Liquid biopsies have a large potential to detect cancer earlier upon initial recurrence and to aid in adjuvant decision making through a non-invasive and highly accurate mechanism. Methods: We developed a 30kb ctDNA capture panel based on the landscape of genomic alterations in ctDNA of over 10,000 advanced cancer patients with high theoretical clinical sensitivity for colorectal (96%) and lung (87-93%) cancers. The panel was validated with high analytical PPV (86% at MAFs < 0.025%, 96% at MAFs > 0.025%). We applied the panel to a clinical study of 63 healthy donors and also 40 early stage (II/III) CRC and lung cancer patients with both pre- and post-tumor resection blood draws. Tumor samples were also collected at the time of the surgical resection. Results: Overall, the detection rate of ctDNA in pre-op blood draws was 72% (13/18) in CRC and 67% (12/18) in lung cancer patients. In the post-op blood draws ctDNA was detectable in 11% (2/18) of CRC and 11% (2/18) of lung cancer cases. For lung cancer patients, the median MAF in pre-op was 0.06% (0.01%-8.47%, n = 51) and in post-op was 0.06% (0.02%-4.14%, n = 38). For CRC patients, the median MAF in pre-op was 0.18% (0.01%-9.26%, n = 51) and in post-op was 0.36% (0.04%-9.5%, n = 18). Sixty-three healthy donor plasma samples were screened at similar cfDNA input amounts and nine (14%) had mutations; the majority of the mutations were also detected in matched leukocyte DNA. To assess a clinically relevant biological false positive background rate in lung cancer patients, screening of cancer-free smokers is ongoing. Conclusions: We have developed a highly sensitive and specific universal assay for the detection of ctDNA in early stage CRC and lung cancer patients without the requirement of a priori knowledge of tumor mutations. This technology allows for a promising non-invasive route for molecular monitoring of residual disease post-surgery and for early detection of relapse compared to traditional methodologies.

scholarly journals Genome-wide identification of urinary cell-free microRNAs for non-invasive detection of bladder cancer

2018 ◽  
Vol 22 (3) ◽  
pp. 2033-2038 ◽  
Author(s):  
Jaroslav Juracek ◽  
Barbora Peltanova ◽  
Jan Dolezel ◽  
Michal Fedorko ◽  
Dalibor Pacik ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Non Invasive ◽  
Genome Wide

scholarly journals Liquid biopsy in early breast cancer. A preliminary report

2019 ◽  
Author(s):  
ANTONIO RULLI ◽  
CINZIA ANTOGNELLI ◽  
ANNAMARIA SIGGILLINO ◽  
VINCENZO TALESA ◽  
ZAYIK SVITLANA ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liquid Biopsy ◽  
Residual Disease ◽  
Early Stage ◽  
Dynamic Monitoring ◽  
Molecular Profile ◽  
Precision Oncology ◽  
Surgical Biopsy ◽  
Post Surgery ◽  
Genetic Landscape

Abstract Background Liquid biopsy (LB) is a technique that utilizes circulating biomarkers from cancer patients to provide information regarding the genetic landscape of the cancer. LB is emerging as an alternative and complementary diagnostic and prognostic tool to surgical biopsy and is expected to provide the tool for the implementation of precision oncology in clinical settings. In fact, it may contribute to enhance understanding of tumor heterogeneity and permitting the dynamic monitoring of treatment responses and genomic variations. Thus, LB is a promising method for the management of cancer, including breast cancer (BC), whose incidence in Italy is progressively increasing. Previous studies focused mainly on patients with advanced-stage BC. In the present study we evaluated the number of circulating tumor cells (CTCs), the quantity of cell free tumor DNA (cftDNA) and the analysis of the mutational profile of DNA from CTCs (ctcDNA) and cftDNA in early stage BC patients. Methods Matched pre- and post-surgery blood samples were collected from 47 early stage BC patients. CTCs enumeration was done using Isoflux system, molecular profile of ctcDNA and cftDNA was performed with the Spotlight 59 Panels kit on a MiSeq Illumina instrument. Results Eighty percent of samples was CTCs-positive, while healthy controls were all CTCs-negative. Forty-four patients provided a pre-surgery and 21 post-surgery sample. By comparing the number of CTCs post-surgery with that of pre-surgery, we found that 66% of patients showed a decreased number of CTCs, 14% of patients continued to have the same number of CTCs, while, interestingly, 19% of patients showed an increased number of CTCs. NGS of ctcDNA and cftDNA showed that 52% of samples had mutations in 9 genes (TP53, CDKN2A, FBXW7, PTPN11, KRAS, NRAS, BRAF, IDH1, ALK) and in 5 genes (PIK3CA, APC ALK, KRAS, TSC1), respectively, with KRAS and ALK overlapping and TP53 being the most frequently mutated gene in ctcDNA analysis. Conclusions LB could facilitate early detection of minimal residual disease, aiding in the initiation of adjuvant therapy to prevent recurrence and progression towards metastasis, enhance individualized treatment and longitudinal screening, thus improving the clinical management and outcome of patients with early BC.

scholarly journals Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tejaswi Iyyanki ◽  
Baozhen Zhang ◽  
Qixuan Wang ◽  
Ye Hou ◽  
Qiushi Jin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Cancer Cell ◽  
Genome Structure ◽  
Transcription Factor Binding ◽  
Specific Gene ◽  
Open Chromatin ◽  
Factor Binding ◽  
3D Genome ◽  
Genome Wide

Abstract Muscle-invasive bladder cancers are characterized by their distinct expression of luminal and basal genes, which could be used to predict key clinical features such as disease progression and overall survival. Transcriptionally, FOXA1, GATA3, and PPARG are shown to be essential for luminal subtype-specific gene regulation and subtype switching, while TP63, STAT3, and TFAP2 family members are critical for regulation of basal subtype-specific genes. Despite these advances, the underlying epigenetic mechanisms and 3D chromatin architecture responsible for subtype-specific regulation in bladder cancer remain unknown. Result We determine the genome-wide transcriptome, enhancer landscape, and transcription factor binding profiles of FOXA1 and GATA3 in luminal and basal subtypes of bladder cancer. Furthermore, we report the first-ever mapping of genome-wide chromatin interactions by Hi-C in both bladder cancer cell lines and primary patient tumors. We show that subtype-specific transcription is accompanied by specific open chromatin and epigenomic marks, at least partially driven by distinct transcription factor binding at distal enhancers of luminal and basal bladder cancers. Finally, we identify a novel clinically relevant transcription factor, Neuronal PAS Domain Protein 2 (NPAS2), in luminal bladder cancers that regulates other subtype-specific genes and influences cancer cell proliferation and migration. Conclusion In summary, our work identifies unique epigenomic signatures and 3D genome structures in luminal and basal urinary bladder cancers and suggests a novel link between the circadian transcription factor NPAS2 and a clinical bladder cancer subtype.

scholarly journals Current status of ctDNA in precision oncology for hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yan Li ◽  
Yuanyuan Zheng ◽  
Liwei Wu ◽  
Jingjing Li ◽  
Jie Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Diagnostic Technique ◽  
Response Assessment ◽  
Selection Response ◽  
Circulating Tumor Dna ◽  
Current Status ◽  
Precision Oncology ◽  
Tumor Biopsy ◽  
Non Invasive

AbstractThe conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

scholarly journals Alterations of 5-hydroxymethylation in circulating cell-free DNA reflect molecular distinctions of subtypes of non-Hodgkin lymphoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brian C.-H. Chiu ◽  
Chang Chen ◽  
Qiancheng You ◽  
Rudyard Chiu ◽  
Girish Venkataraman ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
Cell Free Dna ◽  
Invasive Approach ◽  
Non Invasive ◽  
Signature Genes ◽  
Non Hodgkin Lymphoma ◽  
Free Dna ◽  
Genome Wide ◽  
Circulating Cell Free Dna

AbstractThe 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

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