TY - JOUR
T1 - Primary constitutional MLH1 epimutations: 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
Y1 - 2018
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.
KW - Cancer
KW - Cancer
UR - http://hdl.handle.net/10807/147851
U2 - 10.1038/s41416-018-0019-8
DO - 10.1038/s41416-018-0019-8
M3 - Article
SN - 0007-0920
SP - 978
EP - 987
JO - British Journal of Cancer
JF - British Journal of Cancer
ER -