Multivariable mixture cure model results for <i>XRCC3</i> rs861539 after adjusting for significant baseline characteristics.

<p>Multivariable mixture cure model results for <i>XRCC3</i> rs861539 after adjusting for significant baseline characteristics.</p

Multivariable mixture cure model results for <i>TYMS</i> rs34743033 after adjusting for significant baseline characteristics.

<p>Multivariable mixture cure model results for <i>TYMS</i> rs34743033 after adjusting for significant baseline characteristics.</p

Candidate polymorphisms investigated in the patient cohort.

<p>Candidate polymorphisms investigated in the patient cohort.</p

Time-dependent ROC curves at 3-, 5-, 7-, and 9-year follow-up times.

<p>A slight but consistent improvement can be seen comparing models containing the either or both of the polymorphisms to Model 1 at different time-points after diagnosis. Model 1) significant baseline characteristics only, Model 2) rs861539 + significant baseline characteristics, Model 3) rs34743033 + significant baseline characteristics, and Model 4) rs861539 + rs34743033 + significant baseline characteristics. ROC: receiver operator characteristic, AUC: area under the ROC curve.</p

Logistic regression model results for MSI status with various predictor combinations in the combined data.

<p>Age at diagnosis, sex, and location are covariates common to all the models described above. IHC refers to the MLH1 immunohistochemical staining variable, CH3 refers to the <i>MLH1</i> promoter methylation variable, AIC  =  Akaike's information criterion. Logistic regression models for each SNP per study population and for the combined data are shown in <b>Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013314#pone.0013314.s003" target="_blank">File S3</a></b>.</p><p>The role of three SNPs of interest, rs1800734, rs749072, and rs13098279, is explored.</p

Single marker analysis in the combined data for 3 SNPs for CRC cases versus controls, <i>MLH1</i> promoter methylation, MLH1 IHC staining and MSI tumor status.

<p>Analyses of CRC cases versus controls are adjusted for age, sex, and site.</p><p>OR  =  odds ratio, CI  =  confidence interval.</p><p>Single marker results for the above SNPs for each study population are shown in <b>Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013314#pone.0013314.s002" target="_blank">File S2</a></b>.</p

Region of chromosome 3 examined with genes and 3 SNPs.

<p>A total of 99 polymorphisms were examined in the Ontario samples across a 500kb region of chromosome 3 surrounding the <i>MLH1</i> gene. Genes in this region are outlined (top panel) along with their transcriptional directionality (bottom panel). The three polymorphisms of interest are indicated. Modified from Ensembl (<a href="http://www.ensembl.org" target="_blank">www.ensembl.org</a>).</p

Proposed model for genetic susceptibility to DNA methylation in sporadic MSI-H CRCs.

<p>Specific SNPs predispose the region, including the <i>MLH1</i> gene promoter, to methylation, which results in promoter silencing and loss of <i>MLH1</i> gene expression that is measured by immunohistochemical staining. Loss of the <i>MLH1</i> gene expression leads to genome-wide microsatellite instability and MSI-H colorectal cancer.</p