| Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. | |
| | |
MedLine Citation:
|
PMID: 18301449 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Monika Morak; Hans Konrad Schackert; Nils Rahner; Beate Betz; Matthias Ebert; Constanze Walldorf; Brigitte Royer-Pokora; Karsten Schulmann; Magnus von Knebel-Doeberitz; Wolfgang Dietmaier; Gisela Keller; Brigitte Kerker; Gertraud Leitner; Elke Holinski-Feder |
Related Documents
:
|
1586529 - Family therapy in general practice: views of referrers and clients. 17868909 - Inheritance of microtia in the finnish population. 15313809 - Kindler syndrome in native americans from panama: report of 26 cases. 15030689 - Probable secondary infections in households of sars patients in hong kong. 17508949 - Information needs following a diagnosis of oesophageal cancer; self-perceived informati... 10584419 - Identification of familial hypercholesterolemia in taiwan: report of eleven cases. 1935299 - Fever, hyperdynamic shock, and multiple-system organ failure. a pseudo-sepsis syndrome ... 15228569 - Intussusception in neonates: analysis of 14 japanese patients. 20579119 - The prime project: developing a patient evidence-base. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-02-27 |
Journal Detail:
|
Title: European journal of human genetics : EJHG Volume: 16 ISSN: 1018-4813 ISO Abbreviation: Eur. J. Hum. Genet. Publication Date: 2008 Jul |
Date Detail:
|
Created Date: 2008-06-19 Completed Date: 2008-09-16 Revised Date: 2008-11-21 |
Medline Journal Info:
|
Nlm Unique ID: 9302235 Medline TA: Eur J Hum Genet Country: England |
Other Details:
|
Languages: eng Pagination: 804-11 Citation Subset: IM |
Affiliation:
|
Department of Internal Medicine, Campus Innenstadt, University Hospital of the Ludwig-Maximilians-University, Munich, Germany. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adaptor Proteins, Signal Transducing
/
genetics* Alleles Base Sequence Blood Cells / pathology* Colorectal Neoplasms, Hereditary Nonpolyposis / genetics* CpG Islands / genetics DNA Methylation* DNA Mutational Analysis DNA, Complementary / genetics DNA, Neoplasm / genetics Family Female Humans Inheritance Patterns / genetics* Male Middle Aged Molecular Sequence Data Mutation / genetics* Nuclear Proteins / genetics* Phenotype Promoter Regions, Genetic / genetics* Sulfites / metabolism |
| Chemical | |
Reg. No./Substance:
|
0/Adaptor Proteins, Signal Transducing; 0/DNA, Complementary; 0/DNA, Neoplasm; 0/MLH1 protein, human; 0/Nuclear Proteins; 0/Sulfites; 15181-46-1/hydrogen sulfite |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.
Next Document: An approach for cutting large and complex pedigrees for linkage analysis.