A multi-centre randomized trial comparing Radiofrequency Ablation with Radical Endoscopic Resection for treatment of Barrett’s Esophagus with High-grade Dysplasia or Early Cancer.
Ontology highlight
ABSTRACT:
DISEASE(S): Intramucosal Cancer,High-grade Intraepithelial Neoplasia,High-grade Dysplasia,Barrett Neoplasie,Barrett Esophagus,Hoogradige Intraepitheliale Neoplasie,Intestinale Metaplasie,Barrett Neoplasia,Intestinal Metaplasia.barrett Slokdarm,Hooggradige Dysplasie
PROVIDER: 15714 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Barrett’s esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of non-dysplastic Barrett’s esophagus (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high grade dysplasia (HGD) or EAC.
2023-01-08 | GSE210647 | GEO
Project description:Barrett’s esophagus is a precancerous lesion that confers a significant risk of esophageal adenocarcinoma. Strategies for selective eradication of Barrett’s have been stymied by our inability to identify the Barrett’s stem cell. Here we employ novel technologies to clone patient-matched stem cells of Barrett’s, gastric, and esophageal epithelium. Genomic analyses of Barrett’s stem cells reveal a patient-specific mutational spectrum ranging from low somatic variation similar to patient-matched gastric epithelial stem cells to ones marked by extensive heterozygous alteration of genes implicated in tumor suppression, epithelial planarity, and epigenetic regulation. Transplantation of transformed Barrett’s stem cells yields tumors with hallmarks of esophageal adenocarcinoma, whereas transformed esophageal stem cells yield squamous cell carcinomas. Thus Barrett’s develops from cells distinct from local eponymous epithelia, emerges without obvious driver mutations, and likely progresses through and from the generation of dominant clones. These findings define a stem cell target for preemptive therapies of a precancerous lesion.
2015-10-01 | GSE49292 | GEO
Project description:The hypotheses are: 1) the intestinal stem cell marker, DCLK1, which is increased in both the epithelium and stroma in colon cancer is also increased in BE (Barrett’s esophagus) with HGD (high grade dysplasia) and in EAC (esophageal adenocarcinoma), 2) this expression correlates with disease progression towards EAC and 3) eradication of cells expressing stem cell markers occurs after therapy of EMR (endoscopic mucosal resection) or RFA (radiofrequency ablation) to eradicate BE with HGD and intramucosal adenocarcinoma and esophagectomy for EAC. We will test our hypotheses with the following aims: 1) To characterize the cell specific expression patterns of intestinal stem cell biomarkers in BE patients and correlate them with serum expression and disease progression, 2) To examine prospectively the effects of EMR, RFA or esophagectomy on the expression of stem cell biomarkers and the progression to EAC.
| 2273018 | ecrin-mdr-crc
Project description:mucosal biopsies were taken from patients at pre and post-argon plasma coagulation (APC) ablation of Barrett's oesophagus, and from healthy controls. Total RNA was extracted using Trizol. miRNA was reversed transcribed using a TaqMan® microRNA Reverse Transcription Kit (Life technologies, #4366596). miRNA profiling was performed with a high throughput TaqMan® OpenArray® Human microRNA panel (Life technologies, #4461104). The panel consisted of probes for 754 human miRNAs that are based on miRNA sequences derived from Sanger miRBase v14. Endoscopic surveillance remains the mainstay of cancer prevention in individuals with Barrett’s oesophagus, and definitive management by surgery or endoscopy is reserved for high grade dysplasia or cancer. There are several endoscopic treatments that are widely used for Barrett’s oesophagus, including argon plasma coagulation (APC). The normality of the regenerated neosquamous epithelium after ablation has been called into question. In the current study we profiled global microRNA expression in oesophageal mucosa before and after ablation of Barrett’s oesophagus using Argon plasma coagulation. Our aim was to investigate differences in microRNA expression between neosquamous and normal squamous tissues.
2017-09-14 | GSE94854 | GEO
Project description:Background & Aims: Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett’s esophagus, the distal esophageal mucosa acquires predominantly intestinal character, with notable gastric features, and is predisposed to develop invasive cancers. We sought to understand the chromatin underpinnings of Barrett’s metaplasia and why it commonly displays simultaneous gastric and intestinal properties. Methods: We profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Mutations in Barrett’s esophagus were examined in relation to tissue-specific enhancer landscapes using a random-forest machine learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett’s biopsy specimens using the assay for transposase-accessible chromatin (ATAC-seq). We used one- and two-color immunohistochemistry to examine protein expression of tissue-restricted genes. Results: Barrett’s esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett’s metaplasia co-express gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins, CLDN18, and a novel gastric marker, ANXA10, revealed extensive tissue and sub-clonal heterogeneity of dual stomach-intestinal cell states. Conclusions: These findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett’s esophagus. Pervasive intra-gland variation argues against stem-cell governance of this phenotype.
2021-06-03 | GSE97178 | GEO
Project description:Introduction: The identification of biomarkers in Barrett’s oesophagus (BO) that stratify groups at risk of progressing to oesophageal adenocarcinoma (OAC) would allow tailored surveillance strategies. We have applied a novel high throughput RNA sequencing analysis characterizing the BO mRNA transcriptome across the metaplasia-dysplasia sequence to identify potential markers of progression in an unbiased fashion and functionally validated these at the protein level. Methods: Matched biopsy samples for histology and RNA extraction were taken from BO patients of known histological grade. RNA was extracted from matched samples and sequenced to 60bp length (paired-end).21 samples were sequenced (HGD,7; LGD, 7 and SIM, 7). Reads obtained were mapped to NCBI build37.2 using TopHat. Read count generation, normalisation and differential expression (DE) analysis was performed using the HTSeq-DESeq pipeline. Significantly DE genes (>2 fold change in expression with B-H adjusted p-value <0.1) were further assessed for network and biological relevance using Ingenuity Pathway analysis. Candidate genes were selected and validated in a larger cohort (n=64) using RT-PCR. Targets were further validated (by ELISA and immunohistochemistry) in independent cohorts of patients using serum and tissue microarrays. Results: DE analysis was performed in 3 groups with 2 conditions at a time using the lower grade cohort as control and the higher grade as comparator: SIM vs. LGD (demonstrated 218 DE genes, 131 up-regulated in LGD, 87 down-regulated compared to SIM), SIM vs. HGD (49 DE, 27 up, 22 down) and LGD vs. HGD (317 DE, 81 up, 216 down). Six network-central candidate genes (FOSB, IL-1B, SERPINA3, KLK7, GSTM5 &SCUBE2) were selected for RT-PCR validation following network and functional analysis. Circulating IL-1β and SERPINA-3 demonstrated progressive significant increases in expression across the dysplasia sequence to OAC (p<0.005)). This was confirmed at the tissue level showing significant differences between SIM and dysplastic BO (p<0.05). Conclusion: The use of RNA-sequencing as a detailed and unbiased analysis method identifies IL-1β and SERPINA-3 as novel candidates differentially expressed along the metaplasia-dysplasia-cancer sequence in BO.
2015-10-01 | GSE58963 | GEO
Project description:Barrett’s esophagus is a condition in which the squamous epithelium of the esophagus is replaced with a metaplastic crypt-structured epithelium and progresses to esophageal adenocarcinoma in a minority of cases. It is an ideal human system in which to study the evolutionary dynamics of progression. Previous results suggested that there is a low mutation rate in Barrett’s, based on measures of whole biopsies. However, it was unclear if this was due to a low mutation rate in crypts or a high mutation rate in crypts with a low clonal expansion rate. We used phylogenetic analyses to study copy-number alterations in the epithelium of 67 whole biopsies and 291 single crypts from those biopsies in 8 individuals with Barrett’s esophagus, including 4 cancer progressors. While crypts contained some private mutations, the mutation load and inferred mutation rate in crypts were similar to those in whole biopsies; the latter thus being a reasonable substrate for studies of the mutational process. Diversity between biopsies and within biopsies were strongly correlated. Mutations were more frequent near the gastro-esophageal junction and genomic instability appeared to precede genome doubling, leading to clonal expansions in two cases. This suggests that progression is driven by rare, carcinogenic alterations of large effect, rather than the gradual accumulation of many alterations of small effect, and explains why most patients with Barrett’s esophagus do not progress to esophageal adenocarcinoma. These results shed light on the evolutionary dynamics underlying neoplastic progression in Barrett’s esophagus. Batch 5 of 7
2018-01-30 | GSE99270 | GEO
Project description:Barrett’s esophagus is a condition in which the squamous epithelium of the esophagus is replaced with a metaplastic crypt-structured epithelium and progresses to esophageal adenocarcinoma in a minority of cases. It is an ideal human system in which to study the evolutionary dynamics of progression. Previous results suggested that there is a low mutation rate in Barrett’s, based on measures of whole biopsies. However, it was unclear if this was due to a low mutation rate in crypts or a high mutation rate in crypts with a low clonal expansion rate. We used phylogenetic analyses to study copy-number alterations in the epithelium of 67 whole biopsies and 291 single crypts from those biopsies in 8 individuals with Barrett’s esophagus, including 4 cancer progressors. While crypts contained some private mutations, the mutation load and inferred mutation rate in crypts were similar to those in whole biopsies; the latter thus being a reasonable substrate for studies of the mutational process. Diversity between biopsies and within biopsies were strongly correlated. Mutations were more frequent near the gastro-esophageal junction and genomic instability appeared to precede genome doubling, leading to clonal expansions in two cases. This suggests that progression is driven by rare, carcinogenic alterations of large effect, rather than the gradual accumulation of many alterations of small effect, and explains why most patients with Barrett’s esophagus do not progress to esophageal adenocarcinoma. These results shed light on the evolutionary dynamics underlying neoplastic progression in Barrett’s esophagus. Batch 4 of 7
2018-01-30 | GSE99269 | GEO
Project description:Barrett’s esophagus is a condition in which the squamous epithelium of the esophagus is replaced with a metaplastic crypt-structured epithelium and progresses to esophageal adenocarcinoma in a minority of cases. It is an ideal human system in which to study the evolutionary dynamics of progression. Previous results suggested that there is a low mutation rate in Barrett’s, based on measures of whole biopsies. However, it was unclear if this was due to a low mutation rate in crypts or a high mutation rate in crypts with a low clonal expansion rate. We used phylogenetic analyses to study copy-number alterations in the epithelium of 67 whole biopsies and 291 single crypts from those biopsies in 8 individuals with Barrett’s esophagus, including 4 cancer progressors. While crypts contained some private mutations, the mutation load and inferred mutation rate in crypts were similar to those in whole biopsies; the latter thus being a reasonable substrate for studies of the mutational process. Diversity between biopsies and within biopsies were strongly correlated. Mutations were more frequent near the gastro-esophageal junction and genomic instability appeared to precede genome doubling, leading to clonal expansions in two cases. This suggests that progression is driven by rare, carcinogenic alterations of large effect, rather than the gradual accumulation of many alterations of small effect, and explains why most patients with Barrett’s esophagus do not progress to esophageal adenocarcinoma. These results shed light on the evolutionary dynamics underlying neoplastic progression in Barrett’s esophagus. Batch 3 of 7
2018-01-30 | GSE99268 | GEO
Project description:Barrett’s esophagus is a condition in which the squamous epithelium of the esophagus is replaced with a metaplastic crypt-structured epithelium and progresses to esophageal adenocarcinoma in a minority of cases. It is an ideal human system in which to study the evolutionary dynamics of progression. Previous results suggested that there is a low mutation rate in Barrett’s, based on measures of whole biopsies. However, it was unclear if this was due to a low mutation rate in crypts or a high mutation rate in crypts with a low clonal expansion rate. We used phylogenetic analyses to study copy-number alterations in the epithelium of 67 whole biopsies and 291 single crypts from those biopsies in 8 individuals with Barrett’s esophagus, including 4 cancer progressors. While crypts contained some private mutations, the mutation load and inferred mutation rate in crypts were similar to those in whole biopsies; the latter thus being a reasonable substrate for studies of the mutational process. Diversity between biopsies and within biopsies were strongly correlated. Mutations were more frequent near the gastro-esophageal junction and genomic instability appeared to precede genome doubling, leading to clonal expansions in two cases. This suggests that progression is driven by rare, carcinogenic alterations of large effect, rather than the gradual accumulation of many alterations of small effect, and explains why most patients with Barrett’s esophagus do not progress to esophageal adenocarcinoma. These results shed light on the evolutionary dynamics underlying neoplastic progression in Barrett’s esophagus. Batch 2 of 7
2018-01-30 | GSE99267 | GEO