Primary constitutional MLH1 epimutations: a focal epigenetic event
| Autor: | Daniel Rueda, Gabriel Capellá, Adela Castillejo, Estela Dámaso, Megan P. Hitchins, Julia Canet-Hermida, Marta Pineda, Angel Alonso, Matilde Navarro, Jesús del Valle, Anna Fernández, Fátima Marín, José Luis Soto, Juan de Dios García-Díaz, Daniela Turchetti, Conxi Lázaro, Maurizio Genuardi, Olga Campos, María del Mar Arias |
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| Přispěvatelé: | Dámaso, Estela, Castillejo, Adela, Arias, María del Mar, Canet-Hermida, Julia, Navarro, Matilde, del Valle, Jesú, Campos, Olga, Fernández, Anna, Marín, Fátima, Turchetti, Daniela, García-Díaz, Juan de Dio, Lázaro, Conxi, Genuardi, Maurizio, Rueda, Daniel, Alonso, Ángel, Soto, Jose Lui, Hitchins, Megan, Pineda, Marta, Capellá, Gabriel |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Cancer Research Locus (genetics) Biology Settore MED/03 - GENETICA MEDICA MLH1 Article Epigenesis Genetic Epigènesi 03 medical and health sciences 0302 clinical medicine medicine Humans Genetic Predisposition to Disease Epigenetics Allele Promoter Regions Genetic neoplasms Cancer Epigenesis Genetics Base Sequence Mutació (Biologia) nutritional and metabolic diseases Sequence Analysis DNA Methylation DNA Methylation Mutation (Biology) medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis digestive system diseases Lynch syndrome 030104 developmental biology Haplotypes Oncology CpG site 030220 oncology & carcinogenesis Mutation CpG Islands Female Colorectal Neoplasms MutL Protein Homolog 1 |
| Zdroj: | BRITISH JOURNAL OF CANCER r-ISABIAL: Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL) Dipòsit Digital de la UB Universidad de Barcelona r-FISABIO: Repositorio Institucional de Producción Científica Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante instname r-FISABIO. Repositorio Institucional de Producción Científica British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility. |
| Databáze: | OpenAIRE |
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