Dámaso, EstelaGonzález Acosta, María IsabelVargas Parra, Gardenía MaríaNavarro, MatildeBalmaña, JudithRamon y Cajal, TeresaTuset, NoemíThompson, Bryony A.Marín, FátimaFernández, AnnaGomez, CarolinaVelasco, ÀngelaSolanes, AresIglesias Casals, SílviaUrgel, GiselaLópez, ConsolValle, Jesús delCampos, OlgaSantacana, MariaMatias-Guiu, Xavier, 1958-Lázaro García, ConxiValle, LauraBrunet, JoanPineda Riu, MartaCapellá, G. (Gabriel)2020-11-042020-11-042020-07-01https://hdl.handle.net/2445/171747The 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.25 p.application/pdfengcc by (c) Dámaso et al., 2020http://creativecommons.org/licenses/by/3.0/es/Càncer colorectalGenèticaColorectal cancerGeneticsinfo:eu-repo/semantics/article7070542020-11-03info:eu-repo/semantics/openAccess32635641