{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:14:38Z","timestamp":1790694878691,"version":"4.1.0"},"reference-count":21,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[2008,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>Current models of clonal expansion in human Barrett\u2019s oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett\u2019s segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett\u2019s metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Individual crypts across Barrett\u2019s biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns,\n                      <jats:italic>p16<\/jats:italic>\n                      and\n                      <jats:italic>p53<\/jats:italic>\n                      point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a\n                      <jats:italic>p16<\/jats:italic>\n                      point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett\u2019s dysplasia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>By studying clonality at the crypt level we demonstrate that Barrett\u2019s heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett\u2019s metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gut.2007.143339","type":"journal-article","created":{"date-parts":[[2008,2,27]],"date-time":"2008-02-27T20:58:47Z","timestamp":1204145927000},"page":"1041-1048","source":"Crossref","is-referenced-by-count":184,"title":["Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett\u2019s oesophagus"],"prefix":"10.1136","volume":"57","author":[{"given":"S J","family":"Leedham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S L","family":"Preston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S A C","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Elia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Bhandari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Poller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M R","family":"Novelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J A","family":"Jankowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N 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the origin of cardiac mucosa: a histological and immunohistochemical study of cytokeratin expression patterns in the developing esophagogastric junction region and stomach.","volume":"11","author":"De Hertogh","year":"2005","journal-title":"World J Gastroenterol"},{"key":"2025121223452375000_57.8.1041.15","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1997.v112.pm9041237"},{"key":"2025121223452375000_57.8.1041.16","doi-asserted-by":"publisher","DOI":"10.1002\/path.1804"},{"key":"2025121223452375000_57.8.1041.17","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711730406"},{"key":"2025121223452375000_57.8.1041.18","first-page":"4784","article-title":"p53-mutant clones and field effects in Barrett\u00e2\u0080\u0099s esophagus.","volume":"59","author":"Prevo","year":"1999","journal-title":"Cancer Res"},{"key":"2025121223452375000_57.8.1041.19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/bjs.1800750208","article-title":"Experimental columnar metaplasia in the 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