SNP rs16906252C>T is an expression and methylation quantitative trait locus associated with an increased risk of developing MGMT-methylated colorectal cancer

Kuroiwa-Trzmielina, Joice, Wang, Fan, Rapkins, Robert W., Ward, Robyn L., Buchanan, Daniel D., Win, Aung Ko, Clendenning, Mark, Rosty, Christophe, Southey, Melissa C., Winship, Ingrid M., Hopper, John L., Jenkins, Mark A., Olivier, Jake, Hawkins, Nicholas J. and Hitchins, Megan P. (2016) SNP rs16906252C>T is an expression and methylation quantitative trait locus associated with an increased risk of developing MGMT-methylated colorectal cancer. Clinical Cancer Research, 22 15: 6266-6277. doi:10.1158/1078-0432.CCR-15-2765


Author Kuroiwa-Trzmielina, Joice
Wang, Fan
Rapkins, Robert W.
Ward, Robyn L.
Buchanan, Daniel D.
Win, Aung Ko
Clendenning, Mark
Rosty, Christophe
Southey, Melissa C.
Winship, Ingrid M.
Hopper, John L.
Jenkins, Mark A.
Olivier, Jake
Hawkins, Nicholas J.
Hitchins, Megan P.
Title SNP rs16906252C>T is an expression and methylation quantitative trait locus associated with an increased risk of developing MGMT-methylated colorectal cancer
Formatted title
SNP rs16906252C>T is an expression and methylation quantitative trait locus associated with an increased risk of developing MGMT-methylated colorectal cancer
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2016-08-01
Year available 2016
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-15-2765
Open Access Status Not Open Access
Volume 22
Issue 15
Start page 6266
End page 6277
Total pages 42
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Abstract Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues.

By applying a molecular pathologic epidemiology case-control study design, associations between rs16906252C>T and risk for colorectal cancer overall, and colorectal cancer stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of colorectal cancer cases and controls. The test sample comprised 1,054 colorectal cancer cases and 451 controls from Sydney, Australia. The validation sample comprised 612 colorectal cancer cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine whether rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues.

An association between rs16906252C>T and increased risk of developing MGMT-methylated colorectal cancer in the Sydney sample was observed [OR, 3.3; 95% confidence interval (CI), 2.0-5.3; P < 0.0001], which was replicated in the ACCFR sample (OR, 4.0; 95% CI, 2.4-6.8; P < 0.0001). The T allele demonstrated about 2.5-fold reduced transcription in normal colorectal mucosa from cases and controls and was selectively methylated in a minority of normal cells, indicating that rs16906252C>T represents an expression and methylation quantitative trait locus.

We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated colorectal cancer, likely mediated by constitutive epigenetic repression of the T allele. Clin Cancer Res; 22(24); 6266-77. ©2016 AACR.
Formatted abstract
Purpose: Methylation of the MGMT promoter is the major cause of O6-methylguanine methyltransferase deficiency in cancer and has been associated with the T variant of the promoter-enhancer SNP rs16906252C>T. We sought evidence for an association between the rs16906252C>T genotype and increased risk of developing a subtype of colorectal cancer (CRC) featuring MGMT methylation, mediated by genotype-dependent epigenetic silencing within normal tissues.

Experimental Design: By applying a molecular pathological epidemiology case-control study design, associations between rs16906252C>T and risk for CRC overall, and CRC stratified by MGMT methylation status, were estimated using multinomial logistic regression in two independent retrospective series of CRC cases and controls. The test sample comprised 1054 CRC cases and 451 controls from Sydney, Australia. The validation sample comprised 612 CRC cases and 245 controls from the Australasian Colon Cancer Family Registry (ACCFR). To determine if rs16906252C>T was linked to a constitutively altered epigenetic state, quantitative allelic expression and methylation analyses were performed in normal tissues.

Results:
An association between rs16906252C>T and increased risk of developing MGMT-methylated CRC in the Sydney sample was observed (OR 3.3; 95%CI=2.0-5.3; P<0.0001), which was replicated in the ACCFR sample (OR 4.0; 95%CI=2.4-6.8; P<0.0001). The T allele demonstrated ~2.5-fold reduced transcription in normal colorectal mucosa from cases and controls, and was selectively methylated in a minority of normal cells, indicating rs16906252C>T represents an expression and methylation quantitative trait locus.

Conclusions: We provide evidence that rs16906252C>T is associated with elevated risk for MGMT-methylated CRC, likely mediated by constitutive epigenetic repression of the T allele.
Keyword MGMT
SNP
Methylation
Colorectal cancer
Risk
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID U01 CA097735
U24 CA097735
UM1 CA167551
Institutional Status UQ

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Sub-type: Article (original research)
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Created: Thu, 28 Jul 2016, 00:31:55 EST by Amelie Casgrain on behalf of School of Medicine