Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-defi...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2020-07, Vol.12 (7), p.1799
Main Authors: Dámaso, Estela, González-Acosta, Maribel, Vargas-Parra, Gardenia, Navarro, Matilde, Balmaña, Judith, Ramon Y Cajal, Teresa, Tuset, Noemí, Thompson, Bryony A, Marín, Fátima, Fernández, Anna, Gómez, Carolina, Velasco, Àngela, Solanes, Ares, Iglesias, Sílvia, Urgel, Gisela, López, Consol, Del Valle, Jesús, Campos, Olga, Santacana, Maria, Matias-Guiu, Xavier, Lázaro, Conxi, Valle, Laura, Brunet, Joan, Pineda, Marta, Capellá, Gabriel
Format: Article
Language:English
Subjects:
Cancer
Colorectal carcinoma
Deoxyribonucleic acid
DNA
DNA methylation
Epigenetics
Genes
Genetic analysis
Genetic counseling
Genomes
Mismatch repair
MLH1 protein
Mutation
Pathogenicity
Protein expression
Proteins
Software
Splicing
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12071799