Abstract
BackgroundWe 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.Methodology/Principal FindingsWe 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 immunohisotchemistry 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).Conclusions/SignificanceThe observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both.
Highlights
Colorectal cancer (CRC) is the fourth most common cancer, and second leading cause of cancer-related deaths in North America [1]
MLH1 IHC staining was undertaken on 709 Ontario, 462 Newfoundland, and 517 Seattle cases, and MLH1 promoter methylation analysis was performed on 569 Ontario, 468 Newfoundland, and 210 Seattle cases
General clinical and pathologic features of CRC of our total case populations were similar to those of case populations used in the multiple logistic regression models, with the exception of Seattle, where there was a bias towards microsatellite instability (MSI)-H tumors
Summary
Colorectal cancer (CRC) is the fourth most common cancer, and second leading cause of cancer-related deaths in North America [1]. The mutator pathway, on the other hand, accounts for ,15–20% of CRC cases and results from a deficiency of the mismatch-repair (MMR) system, which leads to genome-wide microsatellite instability (MSI) [2,3]. CIMP-positive CRC tumors can be subsequently subdivided into two groups, a more common CIMP1 tumors, which are MSI-H due to MLH1 promoter methylation, and CIMP2 tumors, which are MSS [5]. 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. 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 to genome-wide microsatellite instability
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