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Aberrantly Methylated CDKN2A, MGMT, and MLH1 in Colon Polyps and in Fecal DNA from Patients with Colorectal Polyps

¹ Division of Gastroenterology, Department of Medicine, ² Departments of Pathology, ³ Preventive Medicine, and ⁴ Surgery, Vanderbilt University Medical School; ⁵ Pathology Service and ⁶ Medical Service, Department of Veterans Affairs Tennessee Valley Health Care System, Nashville, Tenessee; ⁷ EXACT Sciences, Marlborough, Maryland; ⁸ Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University and Howard Hughes Medical Institute, Cleveland, Ohio; ⁹ Beth Israel Deaconess Medical Center, Boston, Maryland; ¹⁰ Division of Clinical Research, Fred Hutchinson Cancer Research Center; ¹¹ Division of Gastroenterology, Department of Medicine, University of Washington Medical School; and ¹² Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington

Requests for reprints: William M. Grady, Medical Service, Department of Veterans Affairs Puget Sound Health Care System and Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-100, Seattle, WA 98109. Phone: 206-667-1107; Fax: 206-667-2917; E-mail: wgrady{at}fhcrc.org.

Colon cancer is the third leading cause of cancer-related death in the United States, affecting 147,000 people each year. Most colon cancers arise from benign neoplasms and evolve into adenocarcinomas through a stepwise histologic progression sequence that starts from adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations and, more recently, epigenetic alterations have been associated with specific steps in this polyp-adenocarcinoma sequence and likely drive the histologic progression of colon cancer. Consequently, we have assessed in colon adenomas and hyperplastic polyps the methylation status of MGMT, CDKN2A, and MLH1 to determine the timing and frequency of these events in the polyp-carcinoma progression sequence and subsequently to analyze the potential for these methylated genes to be molecular markers for adenomas and hyperplastic polyps. We have found that methylated MGMT, CDKN2A, and MLH1 occur in 49%, 34%, and 7% of adenomas and in 5%, 10%, and 7% of hyperplastic polyps, respectively, and that they are more common in histologically advanced adenomas. Furthermore, analysis of fecal DNA from persons who have undergone colonoscopic exams revealed methylated CDKN2A, MGMT, and MLH1 in fecal DNA from 31%, 48%, and 0% of individuals with adenomas and from 16%, 27%, and 10% of individuals with no detectable polyps, respectively. These results show that aberrant methylated genes can be detected frequently in sporadic colon polyps and that they can be detected in fecal DNA. Notably, improvements in the specificity and sensitivity of the fecal DNA-based assays will be needed to make them clinically useful diagnostic tests for polyps.

Key Words: molecular markers • colon cancer • colon adenomas • DNA methylation • CDKN2A/p16 • MGMT • MLH1

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