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Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome

Drini, Musa, Wong, Nicholas C, Scott, Hamish S, Craig, Jeffrey M, Dobrovic, Alexander, Hewitt, Chelsee A, Dow, Christofer, Young, Joanne P, Jenkins, Mark A, Saffery, Richard and Macrae, Finlay A 2011, Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome, PLoS one, vol. 6, no. 2, pp. 1-8, doi: 10.1371/journal.pone.0016831.

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Title Investigating the potential role of genetic and epigenetic variation of DNA methyltransferase genes in hyperplastic polyposis syndrome
Author(s) Drini, Musa
Wong, Nicholas C
Scott, Hamish S
Craig, Jeffrey M
Dobrovic, Alexander
Hewitt, Chelsee A
Dow, Christofer
Young, Joanne P
Jenkins, Mark A
Saffery, Richard
Macrae, Finlay A
Journal name PLoS one
Volume number 6
Issue number 2
Article ID e16831
Start page 1
End page 8
Total pages 8
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2011-02-10
ISSN 1932-6203
Keyword(s) hyperplastic polyposis syndrome (HPS)
colorectal cancer (CRC)
CpG island methylator phenotype (CIMP)
DNA methyltransferase (DNMT)
science & technology
Summary 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.
Language eng
DOI 10.1371/journal.pone.0016831
Field of Research MD Multidisciplinary
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2011, Drini et al.
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30110740

Document type: Journal Article
Collections: School of Medicine
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