Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/73006
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Type: Journal article
Title: Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome
Author: Drini, M.
Wong, N.
Scott, H.
Craig, J.
Dobrovic, A.
Hewitt, C.
Dow, C.
Young, J.
Jenkins, M.
Saffery, R.
Macrae, F.
Citation: PLoS One, 2011; 6(2):e16831:1-e16831:8
Publisher: Public Library of Science
Issue Date: 2011
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
Musa Drini, Nicholas C. Wong, Hamish S. Scott, Jeffrey M. Craig, Alexander Dobrovic, Chelsee A. Hewitt, Christofer Dow, Joanne P. Young, Mark A. Jenkins, Richard Saffery and Finlay A. Macrae
Abstract: BACKGROUND: Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS. METHODS: We utilized high resolution melting (HRM) analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters. RESULTS: No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p<0.01) compared with population controls. The DNMT1, DNMT3A and DNMT3B promoters were unmethylated in all instances. Interestingly, the DNMT3L promoter showed low levels of methylation in polyps and normal colonic mucosa relative to matched disease free cells with methylation level negatively correlated to expression level in normal colonic tissue. DNMT3L promoter hypomethylation was more often found in polyps harbouring KRAS mutations (p = 0.0053). BRAF mutations were common (11 out of 21 polyps), whilst KRAS mutations were identified in 4 of 21 polyps. CONCLUSIONS: Genetic or epigenetic alterations in DNMT genes do not appear to be associated with HPS, but further investigation of genetic variation at rs62106244 is justified given the high frequency of the minor allele in this case series.
Keywords: Humans; Colorectal Neoplasms; Intestinal Polyposis; ras Proteins; Proto-Oncogene Proteins; DNA Methylation; Epigenesis, Genetic; CpG Islands; Nucleic Acid Denaturation; Mutation; Exons; Transition Temperature; Adult; Aged; Aged, 80 and over; Middle Aged; Female; Male; Proto-Oncogene Proteins p21(ras); Promoter Regions, Genetic; DNA (Cytosine-5-)-Methyltransferases
Rights: Copyright: © 2011 Drini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0020117676
DOI: 10.1371/journal.pone.0016831
Appears in Collections:Molecular and Biomedical Science publications

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