SUMMARY BACKGROUND DATA: Duodenogastric-esophageal reflux disease is directly linked to Barrett's esophagus and to the development of esophageal adenocarcinoma. Despite this link, little is known about the mutagenic potential of refluxed material on the esophageal mucosa. We hypothesize that the reflux of gastric and duodenal content causes mutations in esophageal mucosa in vivo. METHODS: Seven Sprague Dawley/Big Blue F1 lacI transgenic rats underwent esophagoduodenostomy (ED) to surgically create duodeno-gastric-esophageal reflux. Fourteen nonoperated rats served as negative (n = 7) and as positive (n = 7/methyl-N-amyl-nitrosamine [MNAN] intraperitoneally) controls. The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay. RESULTS: Gross esophagitis was evident in all operated animals. The frequency of lacI mutations in esophageal mucosal cells of animals with ED was significantly higher, nearly 1.5-fold, than that of nonoperated animals. Nitrosamine administration resulted in a nearly 20-fold increase of lacI mutation frequency. Thirteen mutations were successfully sequenced, 46% occurred at CpG dinucleotide sites and 61% were either C to T or G to A transitions. CONCLUSIONS: The data provide preliminary evidence of the mutagenic potential of bile reflux on esophageal epithelium. The specific mutations are markedly higher than would be expected by chance and are similar to that found in p53 mutations of human esophageal adenocarcinoma, providing a link to human esophageal cancer.
SUMMARY BACKGROUND DATA: Duodenogastric-esophageal reflux disease is directly linked to Barrett's esophagus and to the development of esophageal adenocarcinoma. Despite this link, little is known about the mutagenic potential of refluxed material on the esophageal mucosa. We hypothesize that the reflux of gastric and duodenal content causes mutations in esophageal mucosa in vivo. METHODS: Seven Sprague Dawley/Big Blue F1 lacI transgenic rats underwent esophagoduodenostomy (ED) to surgically create duodeno-gastric-esophageal reflux. Fourteen nonoperated rats served as negative (n = 7) and as positive (n = 7/methyl-N-amyl-nitrosamine [MNAN] intraperitoneally) controls. The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay. RESULTS: Gross esophagitis was evident in all operated animals. The frequency of lacI mutations in esophageal mucosal cells of animals with ED was significantly higher, nearly 1.5-fold, than that of nonoperated animals. Nitrosamine administration resulted in a nearly 20-fold increase of lacI mutation frequency. Thirteen mutations were successfully sequenced, 46% occurred at CpG dinucleotide sites and 61% were either C to T or G to A transitions. CONCLUSIONS: The data provide preliminary evidence of the mutagenic potential of bile reflux on esophageal epithelium. The specific mutations are markedly higher than would be expected by chance and are similar to that found in p53 mutations of humanesophageal adenocarcinoma, providing a link to humanesophageal cancer.
Authors: D J Parks; S G Blanchard; R K Bledsoe; G Chandra; T G Consler; S A Kliewer; J B Stimmel; T M Willson; A M Zavacki; D D Moore; J M Lehmann Journal: Science Date: 1999-05-21 Impact factor: 47.728
Authors: M C Hollstein; L Peri; A M Mandard; J A Welsh; R Montesano; R A Metcalf; M Bak; C C Harris Journal: Cancer Res Date: 1991-08-01 Impact factor: 12.701
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Authors: Katerina Dvorak; George S Watts; Lois Ramsey; Hana Holubec; Claire M Payne; Carol Bernstein; Gareth J Jenkins; Richard E Sampliner; Anil Prasad; Harinder S Garewal; Harris Bernstein Journal: Am J Gastroenterol Date: 2009-01-27 Impact factor: 10.864
Authors: Jonine D Figueroa; Mary Beth Terry; Marilie D Gammon; Thomas L Vaughan; Harvey A Risch; Fang-Fang Zhang; David E Kleiner; William P Bennett; Christine L Howe; Robert Dubrow; Susan T Mayne; Joseph F Fraumeni; Wong-Ho Chow Journal: Cancer Causes Control Date: 2008-11-07 Impact factor: 2.506