Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation
dc.contributor.author
dc.date.accessioned
2020-07-09T09:22:12Z
dc.date.available
2020-07-09T09:22:12Z
dc.date.issued
2019-11-28
dc.identifier.issn
1868-7083
dc.identifier.uri
dc.description.abstract
Constitutional MLH1 methylation (epimutation) is a rare cause of Lynch syndrome. Low-level methylation (≤ 10%) has occasionally been described. This study aimed to identify low-level constitutional MLH1 epimutations and determine its causal role in patients with MLH1-hypermethylated colorectal cancer.
Eighteen patients with MLH1-hypermethylated colorectal tumors in whom MLH1 methylation was previously undetected in blood by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were screened for MLH1 methylation using highly sensitive MS-melting curve analysis (MS-MCA). Constitutional methylation was characterized by different approaches.
MS-MCA identified one patient (5.6%) with low-level MLH1 methylation (~ 1%) in blood and other normal tissues, which was confirmed by clonal bisulfite sequencing in blood. The patient had developed three clonally related gastrointestinal MLH1-methylated tumor lesions at 22, 24, and 25 years of age. The methylated region in normal tissues overlapped with that reported for other carriers of constitutional MLH1 epimutations. Low-level MLH1 methylation and reduced allelic expression were linked to the same genetic haplotype, whereas the opposite allele was lost in patient’s tumors. Mutation screening of MLH1 and other hereditary cancer genes was negative.
Herein, a highly sensitive MS-MCA-based approach has demonstrated its utility for the identification of low-level constitutional MLH1 epigenetic mosaicism. The eventual identification and characterization of additional cases will be critical to ascertain the cancer risks associated with constitutional MLH1 epigenetic mosaicism
dc.description.sponsorship
This work was funded by the Spanish Ministry of Economy and
Competitiveness, which is part of Agencia Estatal de Investigación (AEI), and
co-funded by FEDER funds—a way to build Europe—(grant SAF2012-33636
and SAF2015-68016-R), CIBERONC, the Spanish Association Against Cancer
(080253), and the Government of Catalonia (grants 2014SGR338,
2017SGR1282, and PERIS SLT002/16/0037). ED was supported by a grant from
the Spanish Ministry of Economy and Competitiveness. The Mexican National
Council for Science and Technology (CONACyT) fellowship to GVP. JCH and
FM were supported by CIBERONC, and AF was supported by a grant from
the Catalonia Health Department (SLT002/16/00409). We thank CERCA
Programme / Generalitat de Catalunya for institutional support
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
BioMed Central (BMC)
dc.relation.isformatof
Reproducció digital del document publicat a: https://doi.org/10.1186/s13148-019-0762-6
dc.relation.ispartof
Clinical Epigenetics, 2019, vol. 11, art. núm. 171
dc.relation.ispartofseries
Articles publicats (D-CM)
dc.rights
Attribution 4.0 International
dc.rights.uri
dc.title
Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.type.peerreviewed
peer-reviewed
dc.identifier.eissn
1868-7075