Morak, Monika and Schackert, Hans Konrad and Rahner, Nils and Betz, Beate and Ebert, Matthias and Walldorf, Constanze and Royer-Pokora, Brigitte and Schulmann, Karsten and von Knebel-Doeberitz, Magnus and Dietmaier, Wolfgang and Keller, Gisela and Kerker, Brigitte and Leitner, Gertraud and Holinski-Feder, Elke (2008) Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. EUROPEAN JOURNAL OF HUMAN GENETICS, 16 (7). pp. 804-811. ISSN 1018-4813,
Full text not available from this repository. (Request a copy)Abstract
Germline mutations in mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression are the hallmarks of HNPCC (Lynch syndrome). While somatic MLH1 promoter hypermethylation is generally accepted in the tumorigenesis of sporadic tumours, abnormal MLH1 promoter methylation in normal body cells is controversially discussed as a mechanism predisposing patients to HNPCC. In all 94 patients suspected of HNPCC-syndrome with a mean age of onset of 45.5 years, MLH1-deficiency in their tumours but no germline mutation, underwent methylation-specific PCR-screening for MLH1 promoter methylation. In peripheral blood cells of 12 patients an MLH1 promoter methylation, in seven informative cases allele-specific, was found. Normal colonic tissue, buccal mucosa, and tumour tissue available from three patients also presented abnormal methylation in the MLH1 promoter. The heredity of aberrant methylation is questionable. Pro: MLH1 promoter methylation was found in a patient and his mother giving evidence for a familial predisposition for an epimutation in MLH1. Contra: a de novo set-up of methylation in one patient, a mosaic or incomplete methylation pattern in six patients, and no evidence for inheritance of MLH1 promoter methylation in the remaining families. Our findings provide strong evidence that MLH1 promoter methylation in normal body cells mimics HNPCC and constitutes a pathogenic pre-lesion in MLH1. The identification of hypermethylation as an epigenetic defect has important implications for surveillance recommendations, as these patients should be treated like Lynch syndrome patients, whereas the heritability of methylation is still under investigation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NONPOLYPOSIS COLORECTAL-CANCER; MISMATCH REPAIR; MICROSATELLITE INSTABILITY; GERMLINE EPIMUTATIONS; IMPRINTING MECHANISMS; LYNCH SYNDROME; COLON-CANCER; MS-MLPA; HMLH1; GENE; MLH1; HNPCC; methylation; transmission; epimutation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Oct 2020 09:47 |
| Last Modified: | 28 Oct 2020 09:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30654 |
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