Primary constitutional MLH1 epimutations: a focal epigenetic event

BACKGROUND: 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-dept...

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Autores: Dámaso E, Castillejo, Adela, del Mar Arias, Maria, Canet-Hermida, Julia, Navarro, Matilde, del Valle, Jesus, Campos, Olga, Fernandez, Anna, Marin, Fatima, Turchetti, Daniela, de Dios Garcia-Diaz, Juan, Lazaro, Conxi, Genuardi, Maurizio, Rueda, Daniel, Alonso, Angel, Luis Soto, Jose, Hitchins, Megan, Pineda, Marta, Capella, Gabriel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p2879
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/2879
Access Level:acceso abierto
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network_name_str España
repository_id_str
spelling Primary constitutional MLH1 epimutations: a focal epigenetic eventDámaso ECastillejo, Adeladel Mar Arias, MariaCanet-Hermida, JuliaNavarro, Matildedel Valle, JesusCampos, OlgaFernandez, AnnaMarin, FatimaTurchetti, Danielade Dios Garcia-Diaz, JuanLazaro, ConxiGenuardi, MaurizioRueda, DanielAlonso, AngelLuis Soto, JoseHitchins, MeganPineda, MartaCapella, GabrielBACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP7-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.SPRINGERNATURE2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/2879BRITISH JOURNAL OF CANCERISSN: 00070920ISSNe: 15321827reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p28792026-06-11T12:45:17Z
dc.title.none.fl_str_mv Primary constitutional MLH1 epimutations: a focal epigenetic event
title Primary constitutional MLH1 epimutations: a focal epigenetic event
spellingShingle Primary constitutional MLH1 epimutations: a focal epigenetic event
Dámaso E
title_short Primary constitutional MLH1 epimutations: a focal epigenetic event
title_full Primary constitutional MLH1 epimutations: a focal epigenetic event
title_fullStr Primary constitutional MLH1 epimutations: a focal epigenetic event
title_full_unstemmed Primary constitutional MLH1 epimutations: a focal epigenetic event
title_sort Primary constitutional MLH1 epimutations: a focal epigenetic event
dc.creator.none.fl_str_mv Dámaso E
Castillejo, Adela
del Mar Arias, Maria
Canet-Hermida, Julia
Navarro, Matilde
del Valle, Jesus
Campos, Olga
Fernandez, Anna
Marin, Fatima
Turchetti, Daniela
de Dios Garcia-Diaz, Juan
Lazaro, Conxi
Genuardi, Maurizio
Rueda, Daniel
Alonso, Angel
Luis Soto, Jose
Hitchins, Megan
Pineda, Marta
Capella, Gabriel
author Dámaso E
author_facet Dámaso E
Castillejo, Adela
del Mar Arias, Maria
Canet-Hermida, Julia
Navarro, Matilde
del Valle, Jesus
Campos, Olga
Fernandez, Anna
Marin, Fatima
Turchetti, Daniela
de Dios Garcia-Diaz, Juan
Lazaro, Conxi
Genuardi, Maurizio
Rueda, Daniel
Alonso, Angel
Luis Soto, Jose
Hitchins, Megan
Pineda, Marta
Capella, Gabriel
author_role author
author2 Castillejo, Adela
del Mar Arias, Maria
Canet-Hermida, Julia
Navarro, Matilde
del Valle, Jesus
Campos, Olga
Fernandez, Anna
Marin, Fatima
Turchetti, Daniela
de Dios Garcia-Diaz, Juan
Lazaro, Conxi
Genuardi, Maurizio
Rueda, Daniel
Alonso, Angel
Luis Soto, Jose
Hitchins, Megan
Pineda, Marta
Capella, Gabriel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP7-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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/2879
url https://fisabio.portalinvestigacion.com/publicaciones/2879
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGERNATURE
publisher.none.fl_str_mv SPRINGERNATURE
dc.source.none.fl_str_mv BRITISH JOURNAL OF CANCER
ISSN: 00070920
ISSNe: 15321827
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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