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Histologic features distinguish microsatellite-high from microsatellite-low and microsatellite-stable colorectal carcinomas, but do not differentiate germline mutations from methylation of the MLH1 promoter

The detection of microsatellite-unstable (microsatellite instability (MSI)) colorectal carcinomas (CRCs) has prognostic value and can help screen for Lynch syndrome. We determined which histologic features are associated with MSI status and presence of germline mutation and/or methylation of MLH1 promoter. Patients diagnosed with CRC were offered participation in the Columbus-area hereditary nonpolyposis colorectal cancer syndrome study regardless of age or family history. Tumors were evaluated for MSI using a modified Bethesda panel of microsatellite markers. Methylation status of the MLH1 promoter was evaluated by methylation-specific polymerase chain reaction and bisulfite PCR followed by restriction digestion of tumor DNA. All patients with microsatellite-unstable tumors underwent mutation analysis of the MLH1 , MSH2 , and MSH6 genes by full sequencing of genomic DNA and by multiplex ligation probe assay of MLH1 and MSH2 . Histologic end points were tumor type, grade, percentage of mucin, border, and lymphoid host response. Of the 482 CRCs, 87 were MSI with 69 MSI high (MSI-H), 18 MSI low (MSI-L), and 395 microsatellite stable (MSS). Of 87 MSI tumors, 12 had germline mutations and 34 had methylation of the MLH1 promoter. Younger age, but not histologic features, was significantly associated with a germline mutation. Percentage of mucin, histologic type, grade, and lymphoid host response differed significantly between MSI-H when compared with MSI-L or MSS. No difference was found between MSI-L versus MSS. Histologic features are associated with MSI-H CRC and are helpful to differentiate MSI-H from MSI-L and MSS. These features are not useful to distinguish MSI-L from MSS carcinomas, and those with a deleterious germline hereditary nonpolyposis colorectal cancer syndrome mutation from those with methylation of the MLH1 promoter region. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Pathology Elsevier
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