Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility
| Autor: | Denis Boidin, Michèle Mathieu, Michel Crépin, Fabienne Escande, Marie-Pierre Buisine, Marie-Claire Dieu, Gilles Morin, Sylvie Manouvrier, Sophie Lejeune, Nicole Porchet |
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| Rok vydání: | 2011 |
| Předmět: |
Proband
Adult Male Proto-Oncogene Proteins B-raf congenital hereditary and neonatal diseases and abnormalities Heterozygote Heredity Genetic counseling Biology MLH1 DNA Mismatch Repair Methylation Epigenesis Genetic Cohort Studies Germline mutation Genetics medicine Humans Genetic Predisposition to Disease Genetic Testing Child neoplasms Genetics (clinical) Germ-Line Mutation Genetic testing Adaptor Proteins Signal Transducing Aged medicine.diagnostic_test nutritional and metabolic diseases Nuclear Proteins Sequence Analysis DNA Middle Aged medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis digestive system diseases Lynch syndrome Pedigree MutS Homolog 2 Protein MSH2 DNA mismatch repair Female MutL Protein Homolog 1 |
| Zdroj: | Human mutation. 33(1) |
| ISSN: | 1098-1004 |
| Popis: | Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling. |
| Databáze: | OpenAIRE |
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