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p16^INK4a Promoter Is Hypermethylated at a High Frequency in Esophageal Adenocarcinomas¹

Program in Cancer Biology, Division of Public Health Sciences [D. J. W., M. T. B., B. J. R.], Program in Molecular and Cellular Biology [D. J. W.], and Division of Molecular Medicine [R. S.], Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, and Departments of Biostatistics [M. J. E.], Genetics [B. J. R.], and Medicine, Gastroenterology Division [B. J. R.], University of Washington, Seattle, Washington 98195

Loss of heterozygosity (LOH) of 9p21, which contains the p16^INK4a tumor suppressor gene locus, is one of the most frequent genetic abnormalities in human neoplasia, including esophageal adenocarcinomas. Only a minoity of Barrett's adenocarcinomas with 9p21 LOH have a somatic mutation in the remaining p16 allele, and none have been found to have homozygous deletions. To determine whether p16 promoter hypermethylation may be an alternative mechanism for p16 inactivation in esophageal adenocarcinomas, we examined the methylation status of the p16 promoter in flow-sorted aneuploid cell populations from 21 patients with premalignant Barrett's epithelium or esophageal adenocarcinoma. Using bisulfite modification, primer-extension preamplification, and methylation-specific PCR, we demonstrate that the methylation assay can be performed on 2 ng of DNA (275 cells). Eight of 21 patients (38%) had p16 promoter hypermethylation and 9p21 LOH, including 3 patinets who had only premalignant Barrett's epithelium. Our data suggest that promoter hypermethylation with LOH is a common mechanism for inactivation of p16 in the pathogenesis of esophageal adenocarcinomas.

¹ Supported by NIH Grant RO1CA61202, American Cancer Society Grant EDT2li, and National Institute of General Medical Sciences Medical Scientist Training Program Grant 5T32GM07266.

² To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, 1124 Columbia Street, C1-015, Seattle, WA 98104.

Received 3/19/97. Accepted 5/14/97.

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