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Primary constitutional MLH1 epimutations: a focal epigenetic event
Estela Dámaso1, Adela Castillejo2, María Del Mar Arias3
1Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
British Journal of Cancer
|October 5, 2018
Summary
Primary constitutional MLH1 epimutations originate from a specific epigenetic event at the EPM2AIP1-MLH1 CpG island. This occurs without genetic variants, suggesting a novel mechanism for MLH1 epimutations and Lynch syndrome.
Area of Science:
- Epigenetics
- Genomics
- Cancer Biology
Background:
- Constitutional MLH1 epimutations involve monoallelic methylation and silencing of the MLH1 promoter.
- The underlying mechanism of primary MLH1 epimutations remains unclear.
- This study investigates the molecular basis of constitutional MLH1 epimutations.
Purpose of the Study:
- To characterize constitutional MLH1 epimutations.
- To investigate the aberrantly methylated region around MLH1.
- To explore other genomic loci associated with MLH1 epimutations.
Main Methods:
- Analysis of 12 MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 controls using Infinium 450K array.
- Targeted molecular techniques for characterizing MLH1 epimutation carriers.
- Assessment of inheritance patterns of MLH1 epimutations.
Main Results:
- No cis-acting nucleotide or structural variants were found in 10 carriers.
- Inter-generational methylation erasure was observed in two carriers, indicating a primary epimutation type.
- The EPM2AIP1-MLH1 CpG island was the only differentially methylated region identified.
Conclusions:
- Primary constitutional MLH1 epimutations arise from a focal epigenetic event at the EPM2AIP1-MLH1 CpG island.
- These epimutations occur independently of cis-acting genetic variants.
- Further research is required to understand the mechanism and heritability of MLH1 epimutations.
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