Primary constitutional MLH1 epimutations: a focal epigenetic event

Estela Dámaso, Adela Castillejo, María del Mar Arias, Julia Canet-Hermida, Matilde Navarro, Jesús del Valle, Olga Campos, Anna Fernández, Fátima Marín, Daniela Turchetti, Juan de Dios García-Díaz, Conxi Lázaro, Maurizio Genuardi, Daniel Rueda, Ángel Alonso, Jose Luis Soto, Megan Hitchins, Marta Pineda, Gabriel Capellá

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Pages (from-to)978-987
Number of pages10
JournalBritish Journal of Cancer
Issue number8
StatePublished - 16 Oct 2018
Externally publishedYes

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