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...

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Detalles Bibliográficos
Autores: Dámaso, Estela, González Acosta, María Isabel, Vargas Parra, Gardenía María, Navarro, Matilde, Balmaña, Judith, Ramon y Cajal, Teresa, Tuset, Noemí, Thompson, Bryony A., Marín, Fátima, Fernández, Anna, Gomez, Carolina, Velasco, Àngela, Solanes, Ares, Iglesias Casals, Sílvia, Urgel, Gisela, López, Consol, Valle, Jesús del, Campos, Olga, Santacana, Maria, Matias-Guiu, Xavier, 1958-, Lázaro García, Conxi, Valle, Laura, Brunet, Joan, Pineda Riu, Marta, Capellá, G. (Gabriel)
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/171747
Acceso en línea:https://hdl.handle.net/2445/171747
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Genètica
Colorectal cancer
Genetics
Descripción
Sumario: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 constitutionalMLH1epimutation, 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.

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