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Oesophageal free papers
OC-084 The clonal progression of barrett's oesophagus to oesophageal adenocarcinoma
  1. S Khan1,
  2. S Zeki1,
  3. I Mitchell2,
  4. R Harrison3,
  5. L Dunn4,
  6. S Leedham5,
  7. H Barr6,
  8. N Shepherd7,
  9. T Graham8,
  10. N Wright1,
  11. S McDonald1
  1. 1Department of Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK
  2. 2Department of Surgery, Barnet & Chase Farm NHS Trust, London, UK
  3. 3Department of Histopathology, Leicester General Hospital, Leicester, UK
  4. 4Department of Surgery, Newcastle Royal Infirmary, Newcastle, UK
  5. 5Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, Oxford, UK
  6. 6Department of Surgery, Gloucestershire Royal Hospital, Gloucester, UK
  7. 7Department of Histopathology, Gloucestershire Royal Hospital, Gloucester, UK
  8. 8Center for Evolution and Cancer, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA


Introduction Barrett's oesophagus (BO) is a common premalignant condition, wherein the normal squamous oesophageal epithelium is replaced by a columnar, intestinal phenotype. It is the predominant risk factor for the development of oesophageal adenocarcinoma (OA)1 which develops through a metaplasia: dysplasia: carcinoma sequence. Initial studies suggested that BO lesions were genetically clonal.2 However; our group has shown, by gland micro-dissection, that multiple clones are present within BO and it is therefore a genetically heterotypic disease.3 Furthermore, Maley et al4 have shown that genetic diversity increases the risk of BO progressing to cancer. Here, we demonstrate that although Barrett's dysplasia is polyclonal, oesophageal adenocarcinomas arising from Barrett's are typically clonal.

Methods DNA was macro-dissected from dysplastic and cancerous regions of endoscopic mucosal resection (EMR) and oesophagectomy specimens and screened for mutations in p16INK4A, TP53 and K-RAS. Mutated specimens were serially sectioned; crypts and carcinomas were histologically graded and then micro-dissected using a P.A.L.M. laser capture microscope. DNA was extracted from dissected material and was sequenced for the point mutations identified in the initial screen.

Results Individual glands from 10 specimens (EMRs and oesophagectomies) were laser captured and sequenced for mutations identified as per above. Seven specimens contained TP53 mutations and the three remaining specimens were mutated for p16INK4A. Overall, seven of these specimens contained both mutated and wild type dysplastic glands, with a further one specimen containing three distinct p16INK4Amutation. However, the related cancers from these specimens were monoclonal for a mutated genotype found in the dysplasia. These data show that Barrett's dysplasia is polyclonal but Barrett's adenocarcinoma is monoclonal, suggesting that a cellular competition may be involved in the evolution of Barrett's adenocarcinoma from its surrounding dysplasia.


  1.  Barrett's dysplasia exhibits a mosaic pattern of clones, indicating genetic diversity in Barrett's dysplasia.

  2. Oesophageal adenocarcinomas were monoclonal outgrowths from polyclonal Barrett's dysplasia.

Competing interests None declared.

References 1. Jankowski JA, et al. Gastroenterology 2002;122:588–90.

2. Galipeau, et al. J Natl Cancer Inst 1999;91:2087–95.

3. Leedham, et al. Gut 2008;57:1041–8.

4. Maley C, et al. Nature Genetics 2006;38:468–73.

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