RT Journal Article
T1 Primary constitutional MLH1 epimutations: a focal epigenetic event.
A1 Dámaso, Estela
A1 Castillejo, Adela
A1 Arias, María Del Mar
A1 Canet-Hermida, Julia
A1 Navarro, Matilde
A1 Del Valle, Jesús
A1 Campos, Olga
A1 Fernández, Anna
A1 Marín, Fátima
A1 Turchetti, Daniela
A1 García-Díaz, Juan de Dios
A1 Lázaro, Conxi
A1 Genuardi, Maurizio
A1 Rueda, Daniel
A1 Alonso, Ángel
A1 Soto, Jose Luis
A1 Hitchins, Megan
A1 Pineda, Marta
A1 Capellá, Gabriel
AB 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.
YR 2018
FD 2018-10-04
LK https://hdl.handle.net/10668/25384
UL https://hdl.handle.net/10668/25384
LA en
DS RISalud
RD Apr 6, 2025