Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.
We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromo...
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ftdoajarticles:oai:doaj.org/article:45b1bc6790fc4e3ba3677cd88b67c739 2023-05-15T17:21:55+02:00 Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. Miralem Mrkonjic Nicole M Roslin Celia M Greenwood Stavroula Raptis Aaron Pollett Peter W Laird Vaijayanti V Pethe Theodore Chiang Darshana Daftary Elizabeth Dicks Stephen N Thibodeau Steven Gallinger Patrick S Parfrey H Banfield Younghusband John D Potter Thomas J Hudson John R McLaughlin Roger C Green Brent W Zanke Polly A Newcomb Andrew D Paterson Bharati Bapat 2010-10-01T00:00:00Z https://doi.org/10.1371/journal.pone.0013314 https://doaj.org/article/45b1bc6790fc4e3ba3677cd88b67c739 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC2954166?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0013314 https://doaj.org/article/45b1bc6790fc4e3ba3677cd88b67c739 PLoS ONE, Vol 5, Iss 10, p e13314 (2010) Medicine R Science Q article 2010 ftdoajarticles https://doi.org/10.1371/journal.pone.0013314 2022-12-31T01:34:19Z We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls) and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls) and from Seattle (591 cases, 629 controls). Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter-methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value = 0.72 vs. 2.3×10(-4) when the SNP was examined alone).The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both. Article in Journal/Newspaper Newfoundland Directory of Open Access Journals: DOAJ Articles Newfoundland PLoS ONE 5 10 e13314 |
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English |
topic |
Medicine R Science Q |
spellingShingle |
Medicine R Science Q Miralem Mrkonjic Nicole M Roslin Celia M Greenwood Stavroula Raptis Aaron Pollett Peter W Laird Vaijayanti V Pethe Theodore Chiang Darshana Daftary Elizabeth Dicks Stephen N Thibodeau Steven Gallinger Patrick S Parfrey H Banfield Younghusband John D Potter Thomas J Hudson John R McLaughlin Roger C Green Brent W Zanke Polly A Newcomb Andrew D Paterson Bharati Bapat Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
topic_facet |
Medicine R Science Q |
description |
We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls) and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls) and from Seattle (591 cases, 629 controls). Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter-methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value = 0.72 vs. 2.3×10(-4) when the SNP was examined alone).The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both. |
format |
Article in Journal/Newspaper |
author |
Miralem Mrkonjic Nicole M Roslin Celia M Greenwood Stavroula Raptis Aaron Pollett Peter W Laird Vaijayanti V Pethe Theodore Chiang Darshana Daftary Elizabeth Dicks Stephen N Thibodeau Steven Gallinger Patrick S Parfrey H Banfield Younghusband John D Potter Thomas J Hudson John R McLaughlin Roger C Green Brent W Zanke Polly A Newcomb Andrew D Paterson Bharati Bapat |
author_facet |
Miralem Mrkonjic Nicole M Roslin Celia M Greenwood Stavroula Raptis Aaron Pollett Peter W Laird Vaijayanti V Pethe Theodore Chiang Darshana Daftary Elizabeth Dicks Stephen N Thibodeau Steven Gallinger Patrick S Parfrey H Banfield Younghusband John D Potter Thomas J Hudson John R McLaughlin Roger C Green Brent W Zanke Polly A Newcomb Andrew D Paterson Bharati Bapat |
author_sort |
Miralem Mrkonjic |
title |
Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
title_short |
Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
title_full |
Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
title_fullStr |
Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
title_full_unstemmed |
Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. |
title_sort |
specific variants in the mlh1 gene region may drive dna methylation, loss of protein expression, and msi-h colorectal cancer. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2010 |
url |
https://doi.org/10.1371/journal.pone.0013314 https://doaj.org/article/45b1bc6790fc4e3ba3677cd88b67c739 |
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Newfoundland |
geographic_facet |
Newfoundland |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
PLoS ONE, Vol 5, Iss 10, p e13314 (2010) |
op_relation |
http://europepmc.org/articles/PMC2954166?pdf=render https://doaj.org/toc/1932-6203 1932-6203 doi:10.1371/journal.pone.0013314 https://doaj.org/article/45b1bc6790fc4e3ba3677cd88b67c739 |
op_doi |
https://doi.org/10.1371/journal.pone.0013314 |
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PLoS ONE |
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5 |
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10 |
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e13314 |
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