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 journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)978-987
Number of pages10
JournalBritish Journal of Cancer
Volume119
Issue number8
DOIs
Publication statusPublished - Oct 16 2018

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CpG Islands
Epigenomics
Methylation
Alleles
Hereditary Nonpolyposis Colorectal Neoplasms
Inheritance Patterns
Nucleotides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dámaso, E., Castillejo, A., Arias, M. D. M., Canet-Hermida, J., Navarro, M., del Valle, J., ... Capellá, G. (2018). Primary constitutional MLH1 epimutations: a focal epigenetic event. British Journal of Cancer, 119(8), 978-987. https://doi.org/10.1038/s41416-018-0019-8

Primary constitutional MLH1 epimutations : a focal epigenetic event. / Dámaso, Estela; Castillejo, Adela; Arias, María del Mar; Canet-Hermida, Julia; Navarro, Matilde; del Valle, Jesús; Campos, Olga; Fernández, Anna; Marín, Fátima; Turchetti, Daniela; García-Díaz, Juan de Dios; Lázaro, Conxi; Genuardi, Maurizio; Rueda, Daniel; Alonso, Ángel; Soto, Jose Luis; Hitchins, Megan; Pineda, Marta; Capellá, Gabriel.

In: British Journal of Cancer, Vol. 119, No. 8, 16.10.2018, p. 978-987.

Research output: Contribution to journalArticle

Dámaso, E, Castillejo, A, Arias, MDM, Canet-Hermida, J, Navarro, M, del Valle, J, Campos, O, Fernández, A, Marín, F, Turchetti, D, García-Díaz, JDD, Lázaro, C, Genuardi, M, Rueda, D, Alonso, Á, Soto, JL, Hitchins, M, Pineda, M & Capellá, G 2018, 'Primary constitutional MLH1 epimutations: a focal epigenetic event', British Journal of Cancer, vol. 119, no. 8, pp. 978-987. https://doi.org/10.1038/s41416-018-0019-8
Dámaso E, Castillejo A, Arias MDM, Canet-Hermida J, Navarro M, del Valle J et al. Primary constitutional MLH1 epimutations: a focal epigenetic event. British Journal of Cancer. 2018 Oct 16;119(8):978-987. https://doi.org/10.1038/s41416-018-0019-8
Dámaso, Estela ; Castillejo, Adela ; Arias, María del Mar ; Canet-Hermida, Julia ; Navarro, Matilde ; del Valle, Jesús ; Campos, Olga ; Fernández, Anna ; Marín, Fátima ; Turchetti, Daniela ; García-Díaz, Juan de Dios ; Lázaro, Conxi ; Genuardi, Maurizio ; Rueda, Daniel ; Alonso, Ángel ; Soto, Jose Luis ; Hitchins, Megan ; Pineda, Marta ; Capellá, Gabriel. / Primary constitutional MLH1 epimutations : a focal epigenetic event. In: British Journal of Cancer. 2018 ; Vol. 119, No. 8. pp. 978-987.
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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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T2 - a focal epigenetic event

AU - Dámaso, Estela

AU - Castillejo, Adela

AU - Arias, María del Mar

AU - Canet-Hermida, Julia

AU - Navarro, Matilde

AU - del Valle, Jesús

AU - Campos, Olga

AU - Fernández, Anna

AU - Marín, Fátima

AU - Turchetti, Daniela

AU - García-Díaz, Juan de Dios

AU - Lázaro, Conxi

AU - Genuardi, Maurizio

AU - Rueda, Daniel

AU - Alonso, Ángel

AU - Soto, Jose Luis

AU - Hitchins, Megan

AU - Pineda, Marta

AU - Capellá, Gabriel

PY - 2018/10/16

Y1 - 2018/10/16

N2 - 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.

AB - 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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