scholarly journals Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer

2018 ◽  
Author(s):  
Peter Ulz ◽  
Samantha Perakis ◽  
Qing Zhou ◽  
Tina Moser ◽  
Jelena Belic ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Early Detection ◽  
Transcription Factor Binding ◽  
Patient Specific ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Cell Free Dna ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Free Dna

AbstractDeregulation of transcription factors (TFs) is an important driver of tumorigenesis. We developed and validated a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of early detection of colorectal carcinomas. Our approach for mapping tumor-specific transcription factor bindingin vivobased on blood samples makes a key part of the noncoding genome amenable to clinical analysis.

scholarly journals Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Peter Ulz ◽  
Samantha Perakis ◽  
Qing Zhou ◽  
Tina Moser ◽  
Jelena Belic ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Early Stage ◽  
Transcription Factor Binding ◽  
Patient Specific ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Cell Free Dna ◽  
Factor Binding ◽  
Free Dna

Abstract Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.

scholarly journals Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma

2019 ◽  
Vol 37 (18) ◽  
pp. 1547-1557 ◽  
Author(s):  
Emil Christensen ◽  
Karin Birkenkamp-Demtröder ◽  
Himanshu Sethi ◽  
Svetlana Shchegrova ◽  
Raheleh Salari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Early Detection ◽  
Risk Stratification ◽  
Deep Sequencing ◽  
Therapeutic Efficacy ◽  
Patient Specific ◽  
Cell Free Dna ◽  
Free Dna ◽  
Metastatic Relapse ◽  
Ctdna Analysis

PURPOSE Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence ( P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated with pathologic downstaging ( P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods. CONCLUSION ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

scholarly journals Proteome-Wide Analysis of Disease-Associated SNPs That Show Allele-Specific Transcription Factor Binding

PLoS Genetics ◽  
2012 ◽  
Vol 8 (9) ◽  
pp. e1002982 ◽  
Author(s):  
Falk Butter ◽  
Lucy Davison ◽  
Tar Viturawong ◽  
Marion Scheibe ◽  
Michiel Vermeulen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factor Binding ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Allele Specific

scholarly journals Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression

2016 ◽  
Vol 135 (5) ◽  
pp. 485-497 ◽  
Author(s):  
Marco Cavalli ◽  
Gang Pan ◽  
Helena Nord ◽  
Ola Wallerman ◽  
Emelie Wallén Arzt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Rare Variants ◽  
Transcription Factor Binding ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Allele Specific

scholarly journals Discovering unknown human and mouse transcription factor binding sites and their characteristics from ChIP-seq data

2021 ◽  
Vol 118 (20) ◽  
pp. e2026754118
Author(s):  
Chun-Ping Yu ◽  
Chen-Hao Kuo ◽  
Chase W. Nelson ◽  
Chi-An Chen ◽  
Zhi Thong Soh ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Sequencing Data ◽  
Transcription Start Sites ◽  
Factor Binding ◽  
Quality Control Criterion ◽  
Intergenic Regions ◽  
Human And Mouse

Transcription factor binding sites (TFBSs) are essential for gene regulation, but the number of known TFBSs remains limited. We aimed to discover and characterize unknown TFBSs by developing a computational pipeline for analyzing ChIP-seq (chromatin immunoprecipitation followed by sequencing) data. Applying it to the latest ENCODE ChIP-seq data for human and mouse, we found that using the irreproducible discovery rate as a quality-control criterion resulted in many experiments being unnecessarily discarded. By contrast, the number of motif occurrences in ChIP-seq peak regions provides a highly effective criterion, which is reliable even if supported by only one experimental replicate. In total, we obtained 2,058 motifs from 1,089 experiments for 354 human TFs and 163 motifs from 101 experiments for 34 mouse TFs. Among these motifs, 487 have not previously been reported. Mapping the canonical motifs to the human genome reveals a high TFBS density ±2 kb around transcription start sites (TSSs) with a peak at −50 bp. On average, a promoter contains 5.7 TFBSs. However, 70% of TFBSs are in introns (41%) and intergenic regions (29%), whereas only 12% are in promoters (−1 kb to +100 bp from TSSs). Notably, some TFs (e.g., CTCF, JUN, JUNB, and NFE2) have motifs enriched in intergenic regions, including enhancers. We inferred 142 cobinding TF pairs and 186 (including 115 completely) tethered binding TF pairs, indicating frequent interactions between TFs and a higher frequency of tethered binding than cobinding. This study provides a large number of previously undocumented motifs and insights into the biological and genomic features of TFBSs.

scholarly journals Gene Expression and Regulatory Webwork of POLR2K in Bladder Carcinogenesis by Integrated Bioinformatics Approaches

2020 ◽  
Author(s):  
Liliang Yang ◽  
Kaizhen Wang ◽  
Wenjing Guo ◽  
Xian Chen ◽  
Qinglong Guo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transcription Factor ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Expression Patterns ◽  
Transcription Factor Binding ◽  
Sequencing Data ◽  
Factor Binding

Abstract Background：RNA polymerase II subunit K (POLR2K) belongs to one of the multiple subunits of RNA polymerase II (Pol II), whose biological function is to synthesize mRNA. Aberrant POLR2K expression is related to carcinogenesis. However, POLR2K’s underlying role in bladder cancer has not been explored. In the current study, we intend to analyze the function of POLR2K and its regulatory network within bladder cancer.Methods: Public sequencing data was obtained from GEO and TCGA to investigate POLR2K expression and regulatory network within bladder cancer (BLCA) by using GEPIA and Oncomine as well as cBioPortal online tool. LinkedOmics was employed to identify genes displaying significantly differential expression patterns and to perform GO and KEGG analyses. After differential genes was assigned and ranked, GSEA analyses was performed to obtain target networks for transcription factors, miRNAs, and kinases that could regulate POLR2K–associated gene network. Subsequent functional webwork analyses were used to identify cancer-relevant pathways Moreover, POLR2K gene is verified, by ChIP-seq in MCF-7 cell line , with transcription factor binding evidence in the ENCODE Transcription Factor Binding Site Profiles dataset.Conclusions: The current study implies that POLR2K gene is overexpressed and often amplified in BLCA, providing the first evidence that POLR2K deregulation, in particular increased transcription, may promote BLCA. These findings uncover a unique expression patterns of POLR2K and its potential regulatory networks in BLCA, contributing greatly to study of the role of POLR2K in cancer development.

scholarly journals CpG-depleted promoters harbor tissue-specific transcription factor binding signals—implications for motif overrepresentation analyses

2009 ◽  
Vol 37 (19) ◽  
pp. 6305-6315 ◽  
Author(s):  
Helge G. Roider ◽  
Boris Lenhard ◽  
Aditi Kanhere ◽  
Stefan A. Haas ◽  
Martin Vingron
Keyword(s):  
Transcription Factor ◽  
Transcription Factor Binding ◽  
Tissue Specific ◽  
Specific Transcription Factor ◽  
Factor Binding
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