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Title: Primary constitutional MLH1 epimutations: a focal epigenetic event
Author: Dámaso, Estela
Castillejo, Adela
Arias, María del Mar
Canet Hermida, Júlia
Navarro, Matilde
Valle Domínguez, Jesús del
Campos, Olga
Fernández, Anna
Marín, Fátima
Turchetti, Daniela
García Díaz, Juan de Dios
Lázaro García, Conxi
Genuardi, Maurizio
Rueda, Daniel
Alonso, Ángel
Soto, Jose Luis
Hitchins, Megan
Pineda Riu, Marta
Capellá, G. (Gabriel)
Keywords: Epigènesi
Mutació (Biologia)
Mutation (Biology)
Issue Date: Oct-2018
Publisher: Cancer Research UK
Abstract: 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 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.
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It is part of: British Journal of Cancer, 2018, vol. 119, num. 8, p. 978-987
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ISSN: 0007-0920
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Clíniques)

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