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[Cancer Research 61, 8284-8289, November 15, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

p16INK4a Lesions Are Common, Early Abnormalities that Undergo Clonal Expansion in Barrett’s Metaplastic Epithelium1

David J. Wong2, Thomas G. Paulson2, Laura J. Prevo, Patricia C. Galipeau, Gary Longton, Patricia L. Blount and Brian J. Reid3

Divisions of Human Biology [D. J. W., T. G. P., L. J. P., P. C. G., B. J. R.] and Public Health Sciences [D. J. W., T. G. P., L. J. P., P. C. G., G. L., P. L. B., B. J. R.], Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, and Departments of Medicine, Gastroenterology Division [P. L. B., B. J. R.] and Genetics [B. J. R.], University of Washington, Seattle, Washington 98195

Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma, a cancer of which the incidence has been increasing at an alarming rate in Western countries. p16INK4a lesions occur frequently in esophageal adenocarcinomas but their role in neoplastic progression is not well understood. We detected 9p21 loss of heterozygosity, p16 CpG island methylation, and p16 mutations in biopsies from 57%, 61%, and 15%, respectively, of 107 patients with BE. In contrast, no mutations were found in p14ARF or p15, and methylation was found in only 4% and 13%, respectively. >85% of Barrett’s segments had clones with one (p16+/-) or two (p16-/-) p16 lesions. Both p16+/- and p16-/- clones underwent extensive expansion involving up to 17 cm of esophageal mucosa. The prevalence of established biomarkers in BE, such as 17p (p53) loss of heterozygosity, aneuploidy, and/or increased 4N (tetraploid) populations, increased from 0% to 20% to 44% in patients whose biopsies were p16+/+, p16+/-, and p16-/-, respectively (P < 0.001). Barrett’s segment lengths also increased with change in p16 status with a median of 1.5, 6.0, and 8.0 cm for patients with p16+/+, p16+/-, and p16-/- biopsies, respectively (P < 0.001). We conclude that most Barrett’s metaplasia contains genetic and/or epigenetic p16 lesions and has the ability to undergo clonal expansion, creating a field in which other abnormalities can arise that can lead to esophageal adenocarcinoma.




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