MGMT methylation is associated primarily with the germline CT SNP (rs16906252) in colorectal cancer and normal colonic mucosa

Hawkins, Nicholas J., Lee, James H-F, Wong, Justin J-L, Kwok, Chau-To, Ward, Robyn L. and Hitchins, Megan P. (2009) MGMT methylation is associated primarily with the germline CT SNP (rs16906252) in colorectal cancer and normal colonic mucosa. Modern Pathology, 22 12: 1588-1599. doi:10.1038/modpathol.2009.130


Author Hawkins, Nicholas J.
Lee, James H-F
Wong, Justin J-L
Kwok, Chau-To
Ward, Robyn L.
Hitchins, Megan P.
Title MGMT methylation is associated primarily with the germline CT SNP (rs16906252) in colorectal cancer and normal colonic mucosa
Journal name Modern Pathology   Check publisher's open access policy
ISSN 0893-3952
1530-0285
Publication date 2009-12
Sub-type Article (original research)
DOI 10.1038/modpathol.2009.130
Open Access Status Not Open Access
Volume 22
Issue 12
Start page 1588
End page 1599
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
O 6-methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that restores mutagenic O 6-methylguanine to guanine. MGMT methylation is frequently observed in sporadic colorectal cancer and was recently correlated with the CT allele at SNP rs16906252, within the transcriptional enhancer element of the promoter. MGMT methylation has also been associated with KRAS mutations, particularly GA transitions. We studied 1123 colorectal carcinoma to define the molecular and clinicopathological profiles associated with MGMT methylation. Furthermore, we assessed factors contributing to MGMT methylation in the development of colorectal cancer by studying the allelic pattern of MGMT methylation using SNP rs16906252, and the methylation status of neighbouring genes within 10q26 in selected tumours and matched normal colonic mucosa. MGMT methylation was detected by combined bisulphite restriction analysis in 28% of tumours and was associated with a number of characteristics, including CDKN2A methylation, absent lymphovascular space invasion and KRAS mutations (but not specifically with KRAS GA transitions). In a multivariate analysis adjusted for age and sex, MGMT methylation was associated with the T allele of SNP rs16906252 (P0.0001, OR 5.5, 95% CI 3.8-7.9). Low-level methylation was detected by quantitative methylation-specific PCR in the normal colonic mucosa of cases, particularly those with a correspondingly methylated tumour, as well as controls without neoplasia, and this was also associated with the CT SNP. We show that the T allele at SNP rs16906252 is a key determinant in the onset of MGMT methylation in colorectal cancer, whereas the association of methylation at MGMT and CDKN2A suggests that these loci may be targets of a common mechanism of epigenetic dysregulation.
Keyword MGMT
Methylation
Colorectal cancer
SNP
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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