Microsatellite instability (MSI) and genomic hypermethylation of methylated-in-tumor (MINT) loci are both strong prognostic indicators in a subgroup of patients with sporadic colorectal cancer (CRC... Show moreMicrosatellite instability (MSI) and genomic hypermethylation of methylated-in-tumor (MINT) loci are both strong prognostic indicators in a subgroup of patients with sporadic colorectal cancer (CRC). The present study was designed to determine whether the methylation of MINT loci during the progression of adenoma to CRC is related to MSI in CRC cases. Methylation index (MI) was measured by absolute quantitative assessment of methylated alleles at seven MINT loci in primary CRC with contiguous adenomatous and normal tissues of 79 patients. Results were then validated in primary CRC tissues from an independent group of 54 patients. Increased MI of both MINT loci 1 and 31 was significantly associated with MSI in CRC and was specific for adenoma. Total MI and the number of methylated loci were threefold (P = 0.02) and fivefold (P = 0.004) higher, respectively, in adenomas associated with microsatellitestable CRC versus microsatellite-unstable CRC. MINT MI was found to be correlated with mismatch repair protein expression, MSI, BRAF (V600E) mutation status, mut-L homologue 1 methylation status, and disease-specific survival in the second independent validation group of patients. MI of specific MINT loci may be prognostic indicators of colorectal adenomas that will develop into sporadic microsatellite-unstable CRCs. Increased MINT locus methylation appears to precede MSI and may have utility in defining clinical pathology in the absence of features of malignant invasive tumors. (Am J pathol 2010, 177:2347-2356; DOI: 10.2353/ajpath.2010.091103) Show less
Purpose: Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic... Show morePurpose: Risk assessment for locoregional disease recurrence would be highly valuable in preoperative treatment planning for patients undergoing primary rectal tumor resection. Epigenetic aberrations such as DNA methylation have been shown to be significant prognostic biomarkers of disease outcome. In this study, we evaluated the significance of a quantitative epigenetic multimarker panel analysis of primary tumors to predict local recurrence in rectal cancer patients from a retrospective multicenter clinical trial. Experimental Design: Primary tumors were studied from patients enrolled in the trial who underwent total mesorectal excision for rectal cancer (n = 325). Methylation levels of seven methylated-in-tumor (MINT) loci were assessed by absolute quantitative assessment of methylated alleles. Unsupervised random forest clustering of quantitative MINT methylation data was used to show subclassification into groups with matching methylation profiles. Results: Variable importance parameters [Gini-Index (GI)] of the clustering algorithm indicated MINT3 and MINT17 (GI, 20.2 and 20.7, respectively) to be informative for patient grouping compared with the other MINT loci (highest GI, 12.2). When using this two-biomarker panel, four different patient clusters were identified. One cluster containing 73% (184 of 251) of the patients was at significantly increased risk of local recurrence (hazard ratio, 10.23; 95% confidence interval, 1.38-75.91) in multivariate analysis, corrected for standard prognostic factors of rectal cancer. This group showed a significantly higher local recurrence probability than patients receiving preoperative radiation (P < 0.0001). Conclusion: Quantitative epigenetic subclassification of rectal cancers has clinical utility in distinguishing tumors with increased risk for local recurrence and may help tailor treatment regimens for locoregional control. Clin Cancer Res; 16(10); 2811-8. (C) 2010 AACR. Show less
