Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis

Parham Minoo ¹, Kristi Baker ¹, Rashmi Goswami ¹, George Chong ², William Foulkes ², Andrew Ruszkiewicz ³, Melissa Barker ⁴, Daniel Buchanan ⁴, Joanne Young ⁴ and Jeremy Robin Jass ^1*

¹ Department of Pathology, McGill University, Montreal, Canada
² Department of Human Genetics, SMBD Jewish General Hospital, Montreal, Canada
³ Institute of Medical & Veterinary Science, Adelaide, Australia
⁴ Queensland Institute of Medical Research, Brisbane, Australia

^* To whom correspondence should be addressed. E-mail: jeremy.jass{at}mcgill.ca.

Accepted 31 January 2006

Abstract

Background: Hyperplastic polyposis of the colorectum is a precancerous condition that has been linked with DNA methylation. The polyps in this condition have been distinguished from typical small hyperplastic polyps and re-named sessile serrated adenomas. Sessile serrated adenomas also occur sporadically and appear to be indistinguishable from their counterparts in hyperplastic polyposis.

Aims and Methods: The existence of distinguishing molecular features was explored in a series of serrated polyps and matched normal mucosa from patients with and without hyperplastic polyposis by assessing mutation of BRAF, DNA methylation in 14 markers (MINTs 1, 2 and 31, p16, MGMT, MLH1, RASSF1, RASSF2, NORE1 (RASSF5), RKIP, MST1, DAPK, FAS and CHFR), and immuno-expression of MLH1.

Results: There was more extensive methylation in sessile serrated adenomas from subjects with hyperplastic polyposis (P < 0.0001). A more clear-cut difference in patients with hyperplastic polyposis was the finding of extensive DNA methylation in normal mucosa from proximal colon.

Conclusions: A genetic predisposition may underlie at least some forms of hyperplastic polyposis in which the earliest manifestation may be the hypermethylation of multiple gene promoters in normal colorectal mucosa. Additionally, some of the heterogeneity within hyperplastic polyposis may be explained by different propensities for MLH1 inactivation within polyps.

Keywords: DNA methylation, colorectal cancer, hyperplastic polyposis, serrated polyp

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