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Project description:The low risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma can lead to over-diagnosis and over-treatment of BE patients. This may be addressed through a better understanding of the dynamics surrounding BE malignant progression. Although genetic diversity has been characterized as a marker of malignant development, it is still unclear how BE arises and develops. Here we uncover the evolutionary dynamics of BE at crypt and biopsy levels in eight individuals, including four patients that experienced malignant progression. We assay eight individual crypts and the remaining epithelium by SNP array for each of 6-11 biopsies over 2 time points per patient (358 samples in total). Our results indicate that most Barrett's segments are clonal, with similar number and inferred rates of alterations observed for crypts and biopsies. Divergence correlates with geographical location, being higher near the gastro-esophageal junction. Relaxed clock analyses show that genomic instability precedes and is enhanced by genome doubling. These results shed light on the clinically relevant evolutionary dynamics of BE.
| S-EPMC5824808 | biostudies-literature
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 7 of 7
2018-01-30 | GSE99429 | 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 6 of 7
2018-01-30 | GSE99271 | 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 1 of 7
2018-01-30 | GSE99266 | 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
Project description:Evolution of Barrett's Esophagus through space and time at single-crypt and whole-biopsy levels
| PRJNA388443 | ENA
Project description:BackgroundDysplasia in Barrett's esophagus (BE) biopsies is associated with low observer agreement among general pathologists. Therefore, expert review is advised. We are developing a web-based, national expert review panel for histological review of BE biopsies.ObjectiveThe aim of this study was to create benchmark quality criteria for future members.MethodsFive expert BE pathologists, with 10-30 years of BE experience, weekly handling 5-10 cases (25% dysplastic), assessed a case set of 60 digitalized cases, enriched for dysplasia. Each case contained all slides from one endoscopy (non-dysplastic BE (NDBE), n?=?21; low-grade dysplasia (LGD), n?=?20; high-grade dysplasia (HGD), n?=?19). All cases were randomized and assessed twice followed by group discussions to create a consensus diagnosis. Outcome measures: percentage of 'indefinite for dysplasia' (IND) diagnoses, intra-observer agreement, and agreement with the consensus 'gold standard' diagnosis.ResultsMean percentage of IND diagnoses was 8% (3-14%) and mean intra-observer agreement was 0.84 (0.66-1.02). Mean agreement with the consensus diagnosis was 90% (95% prediction interval (PI) 82-98%).ConclusionExpert pathology review of BE requires the scoring of a limited number of IND cases, consistency of assessment and a high agreement with a consensus gold standard diagnosis. These benchmark quality criteria will be used to assess the performance of other pathologists joining our panel.
| S-EPMC6047285 | biostudies-literature